Variant: NM_002880.3(RAF1):c.-339_-338AG[1]

CA177689

40573 (ClinVar)

Gene: RAF1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: bb1a1ba7-e80d-43d8-8451-8dea25906f40

Approved on: 2019-11-04

Published on: 2019-11-04

HGVS expressions

NM_002880.3:c.-337_-336delAG
NM_002880.3:c.-339_-338AG[1]
NM_002880.3(RAF1):c.-339_-338AG[1]
NM_002880.3:c.-337_-336del
NM_001354689.1:c.-337_-336del
NM_001354691.1:c.-560_-559del
NM_001354692.1:c.-467_-466del
NM_001354693.1:c.-337_-336del
NM_001354694.1:c.-467_-466del
NM_001354695.1:c.-467_-466del
NR_148940.1:n.79_80del
NR_148941.1:n.79_80del
NR_148942.1:n.79_80del
ENST00000251849.8:c.-337_-336del
ENST00000442415.6:c.-337_-336del
NC_000003.12:g.12664125_12664126del
CM000665.2:g.12664125_12664126del
NC_000003.11:g.12705624_12705625del
CM000665.1:g.12705624_12705625del
NC_000003.10:g.12680624_12680625del
NG_007467.1:g.5057_5058del

Benign

• Met criteria codes: BP5 BP7 BP4 BA1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.-339_-338delAG variant in RAF1 is classified as benign because it has been identified in 0.33579% (95% CI of 63/15050) of non-Finnish European alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant is not located within the splice consensus sequence and computational splice site prediction tools do not predict an impact on splicing (BP4, BP7). This variant was identified in 4 individuals with Noonan syndrome who carried additional pathogenic variants in PTPN11 sufficient to explain their clinical presentations (BP5). ACMG/AMP Criteria applied: BA1, BP4, BP5, BP7.

Met criteria codes

• BP5: LMM internal data (SCV000616372.3): 15yo white female with NS het. for PTPN11 c.188A>G (p.Tyr63Cys), classified as Pathogenic by RAS VCEP. Also identified in 3 other individuals with NS and alternate mechanisms for disease, whose variants in PTPN11 were not classified by the RAS VCEP but were pathogenic in ClinVar.
• BP7: Variant is outside the splice consensus sequence, and Alamut predicts no impact to splicing.
• BP4: Splicing not predicted to be impacted by Alamut. REVEL score not provided. Conservation data not applicable to intronic variant.
• BA1: Present in 0.33579% (95% CI of 63/15050) of non-Finnish European alleles in gnomAD