Variant: NM_194248.3(OTOF):c.4463A>T (p.Asp1488Val)

CA142888

48235 (ClinVar)

Gene: OTOF

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: a8aca6bb-9e6a-4371-abb7-4d5ac7d567c7

Approved on: 2025-01-15

Published on: 2025-03-28

HGVS expressions

NM_194248.3:c.4463A>T
NM_194248.3(OTOF):c.4463A>T (p.Asp1488Val)
NC_000002.12:g.26466751T>A
CM000664.2:g.26466751T>A
NC_000002.11:g.26689619T>A
CM000664.1:g.26689619T>A
NC_000002.10:g.26543123T>A
NG_009937.1:g.96948A>T
ENST00000272371.7:c.4463A>T
ENST00000339598.8:c.2162A>T
ENST00000402415.8:c.2222A>T
ENST00000272371.6:c.4463A>T
ENST00000338581.10:c.2162A>T
ENST00000339598.7:c.2162A>T
ENST00000402415.7:c.2393A>T
ENST00000403946.7:c.4463A>T
NM_001287489.1:c.4463A>T
NM_004802.3:c.2162A>T
NM_194248.2:c.4463A>T
NM_194322.2:c.2393A>T
NM_194323.2:c.2162A>T
NM_001287489.2:c.4463A>T
NM_004802.4:c.2162A>T
NM_194322.3:c.2393A>T
NM_194323.3:c.2162A>T

Uncertain Significance

• Met criteria codes: PP3 BS1_Supporting

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1

Evidence submitted by expert panel

Hearing Loss VCEP

The filtering allele frequency (the lower threshold of the 95% of 73/60,014) of the c.4463A>T (p.Asp1488Val) variant in OTOF is 0.122% for Latino/Admixed American alleles in gnomAD v4, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). The REVEL computational prediction tool produced a score of 0.805, which is above the threshold necessary to apply PP3. While this variant has been observed in at least 6 probands with hearing loss, none of these individuals had a second variant identified in OTOF (Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000065239.6). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, PP3. (ClinGen Hearing Loss VCEP specifications version 2; 01.15.2025).

Met criteria codes

• PP3: The REVEL computational prediction tool produced a score of 0.805, which is above the threshold necessary to apply PP3.
• BS1_Supporting: The filtering allele frequency (the lower threshold of the 95% of 73/60,014) of the c.4463A>T (p.Asp1488Val) variant in OTOF is 0.122% for Latino/Admixed American alleles in gnomAD v4.