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NM_002880.4(RAF1):c.94A>G (p.Ile32Val) AND Noonan syndrome and Noonan-related syndrome

Germline classification:
Benign (1 submission)
Last evaluated:
Jun 27, 2019
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000788000.1

Allele description [Variation Report for NM_002880.4(RAF1):c.94A>G (p.Ile32Val)]

NM_002880.4(RAF1):c.94A>G (p.Ile32Val)

Gene:
RAF1:Raf-1 proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.2
Genomic location:
Preferred name:
NM_002880.4(RAF1):c.94A>G (p.Ile32Val)
Other names:
p.I32V:ATA>GTA; NM_002880.3(RAF1):c.94A>G
HGVS:
  • NC_000003.12:g.12618628T>C
  • NG_007467.1:g.50552A>G
  • NM_001354689.3:c.94A>G
  • NM_001354690.3:c.94A>G
  • NM_001354691.3:c.-37A>G
  • NM_001354692.3:c.-37A>G
  • NM_001354693.3:c.94A>G
  • NM_001354694.3:c.-37A>G
  • NM_001354695.3:c.-37A>G
  • NM_002880.4:c.94A>GMANE SELECT
  • NP_001341618.1:p.Ile32Val
  • NP_001341619.1:p.Ile32Val
  • NP_001341622.1:p.Ile32Val
  • NP_002871.1:p.Ile32Val
  • NP_002871.1:p.Ile32Val
  • LRG_413t1:c.94A>G
  • LRG_413t2:c.94A>G
  • LRG_413:g.50552A>G
  • LRG_413p1:p.Ile32Val
  • LRG_413p2:p.Ile32Val
  • NC_000003.11:g.12660127T>C
  • NM_002880.3:c.94A>G
  • NR_148940.3:n.425A>G
  • NR_148941.3:n.425A>G
  • NR_148942.3:n.425A>G
Protein change:
I32V
Links:
dbSNP: rs372738063
NCBI 1000 Genomes Browser:
rs372738063
Molecular consequence:
  • NM_001354691.3:c.-37A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354692.3:c.-37A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354694.3:c.-37A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354695.3:c.-37A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354689.3:c.94A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.3:c.94A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.3:c.94A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.4:c.94A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.3:n.425A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.3:n.425A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.3:n.425A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Noonan syndrome and Noonan-related syndrome
Identifiers:
MONDO: MONDO:0020297; MedGen: C5681679; Orphanet: 98733

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000927032ClinGen RASopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)		Benign
(Jun 27, 2019) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000927032.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.94A>G (p.Ile32Val) variant in the RAF1 gene has been identified in patients who underwent testing for a RASopathy, however it has also been identified in multiple adults who did not have clinical features of a RASopathy (BS2, BP5; Invitae, EGL Diagnostics, GeneDx internal data; GTR Lab ID: 500031, 500060; SCV000287747.4, SCV000227277.5, SCV000209002.14). The filtering allele frequency of the p.Ile32Val variant is 0.017% for European (non-Finnish) genomes in the gnomAD database (8/31404 with 95% CI) which is a high enough frequency to be considered strong evidence that the variant is benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1). Computational prediction tools and conservation analysis suggest that the p.Ile32Val variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS2, BP5, BS1, BP4.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024