rs3730297

Variant names:

• chr3-12584520-G-A
• rs3730297
• NM_002880.4:c.1941C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-12584520-G-A
• chr3-12584520-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1941C>T (p.Val647=) variant in the RAF1 gene is 1.04% (738/66732) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134718/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0070 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (86 hom.)
• Consequence: RAF1 NM_002880.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:14 O:1
• Conservation: PhyloP100: 1.18

Genes affected

RAF1 (HGNC:9829): (Raf-1 proto-oncogene, serine/threonine kinase) This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

MKRN2 (HGNC:7113): (makorin ring finger protein 2) This gene encodes a probable E3 ubiquitin ligase containing several zinc finger domains, that is a member of the makorin RING zinc-finger protein family. This gene overlaps the v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1) gene in an antisense orientation and may have a co-regulatory function with RAF1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.1941C>T	p.Val647Val	synonymous_variant	Exon 17 of 17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.1941C>T	p.Val647Val	synonymous_variant	Exon 17 of 17	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1070 AN: 152194 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00679 AC: 1705 AN: 251226 AF XY: 0.00671

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00726

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.00977 AC: 14286 AN: 1461886 Hom.: 86 Cov.: 31 AF XY: 0.00945 AC XY: 6873 AN XY: 727246

Gnomad4 AFR exome AF: 0.00102 AC: 34 AN: 33480

Gnomad4 AMR exome AF: 0.00445 AC: 199 AN: 44724

Gnomad4 ASJ exome AF: 0.00677 AC: 177 AN: 26136

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39700

Gnomad4 SAS exome AF: 0.00180 AC: 155 AN: 86258

Gnomad4 FIN exome AF: 0.00831 AC: 444 AN: 53420

Gnomad4 NFE exome AF: 0.0115 AC: 12783 AN: 1112004

Gnomad4 Remaining exome AF: 0.00783 AC: 473 AN: 60396

GnomAD4 genome AF: 0.00703 AC: 1070 AN: 152312 Hom.: 3 Cov.: 32 AF XY: 0.00667 AC XY: 497 AN XY: 74490

Gnomad4 AFR AF: 0.00178 AC: 0.0017803 AN: 0.0017803

Gnomad4 AMR AF: 0.0101 AC: 0.0101373 AN: 0.0101373

Gnomad4 ASJ AF: 0.00576 AC: 0.00576369 AN: 0.00576369

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00186 AC: 0.00186335 AN: 0.00186335

Gnomad4 FIN AF: 0.00838 AC: 0.00837884 AN: 0.00837884

Gnomad4 NFE AF: 0.0103 AC: 0.0103184 AN: 0.0103184

Gnomad4 OTH AF: 0.00993 AC: 0.00993377 AN: 0.00993377

Alfa AF: 0.00878 Hom.: 9

Bravo AF: 0.00652

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0100

EpiControl AF: 0.00966

ClinVar

Significance: Benign

Submissions summary: Benign:14 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MKRN2: BS1, BS2; RAF1: BP4, BS1, BS2 -

-

GenomeConnect - CFC International

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-30-2009 by Lab or GTR ID 239772. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines -

Apr 18, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The filtering allele frequency of the c.1941C>T (p.Val647=) variant in the RAF1 gene is 1.04% (738/66732) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -

LEOPARD syndrome 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Dec 08, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome Benign:1

Jul 08, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 5 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.3
DANN	Benign	0.58
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3730297; hg19: chr3-12626019;