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CA10576608

229175 (ClinVar)

Gene: RAF1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: 919f50ca-3d8b-43ff-8ea0-a44b985bc2e3

HGVS expressions

NM_002880.3:c.124_125delGCinsAT
NM_002880.3:c.124_125delinsAT
NM_001354689.1:c.124_125delinsAT
NM_001354690.1:c.124_125delinsAT
NM_001354691.1:c.-7_-6delinsAT
NM_001354692.1:c.-7_-6delinsAT
NM_001354693.1:c.124_125delinsAT
NM_001354694.1:c.-7_-6delinsAT
NM_001354695.1:c.-7_-6delinsAT
NR_148940.1:n.539_540delinsAT
NR_148941.1:n.539_540delinsAT
NR_148942.1:n.539_540delinsAT
ENST00000251849.8:c.124_125delinsAT
ENST00000416093.1:c.124_125delinsAT
ENST00000423275.5:c.124_125delinsAT
ENST00000442415.6:c.124_125delinsAT
NC_000003.12:g.12618597_12618598delinsAT
CM000665.2:g.12618597_12618598delinsAT
NC_000003.11:g.12660096_12660097delinsAT
CM000665.1:g.12660096_12660097delinsAT
NC_000003.10:g.12635096_12635097delinsAT
NG_007467.1:g.50582_50583delinsAT

Likely Benign

Met criteria codes 2
BS1 BP5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.124_125delinsAT (p.Ala42Ile) variant in RAF1 is reported in population databases as two contiguous missense variants: c.124G>A and c.125C>T in cis in 27/64,595 (0.03%) European individuals in gnomAD. This meets the cut off set by the ClinGen RASopathy Variant Curation Expert Panel to apply BS1. This variant has been observed in at least 22 individuals (SCV000858114.1, SCV000698121.1, SCV000272341.3, SCV000552093.5, GeneDx internal data). This variant was observed in an individual with an alternate molecular basis for disease (BP5; SCV000698121.1 ). Computational prediction tools and conservation analysis suggest that the p.Ala42Ile variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5, BP4.
Met criteria codes
BS1
“This variant is reported in population databases as two contiguous missense variants c.124G>A and c.125C>T reported in cis in 27 individuals in population databases (ExAC, 0.04%).” Invitae ClinVar submission. 42/129190 (.03%) European alleles in gnomAD
BP5
7 year old female in whom c.923A>G (p.Asn308Ser) in PTPN11 was also identified (Integrated Genetics internal data).
Approved on: 2019-09-24
Published on: 2019-12-03
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