rs3730296

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.1755A>G (p.Val585=) variant in the RAF1 gene is 6.222% (690/10404) of African 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/CA134709/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.019 ( 95 hom., cov: 32)
Exomes 𝑓: 0.0020 ( 86 hom. )

Consequence

RAF1
NM_002880.4 synonymous

Scores

2

Clinical Significance

Benign reviewed by expert panel B:14

Conservation

PhyloP100: -0.245
Variant links:
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]

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ACMG classification

Classification was made for transcript

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
RAF1NM_002880.4 linkc.1755A>G p.Val585Val synonymous_variant Exon 16 of 17 ENST00000251849.9 NP_002871.1 P04049-1L7RRS6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAF1ENST00000251849.9 linkc.1755A>G p.Val585Val synonymous_variant Exon 16 of 17 1 NM_002880.4 ENSP00000251849.4 P04049-1

Frequencies

GnomAD3 genomes
AF:
0.0194
AC:
2955
AN:
152190
Hom.:
94
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0672
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00883
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.0100
GnomAD2 exomes
AF:
0.00505
AC:
1270
AN:
251380
AF XY:
0.00376
show subpopulations
Gnomad AFR exome
AF:
0.0684
Gnomad AMR exome
AF:
0.00350
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.00277
GnomAD4 exome
AF:
0.00197
AC:
2880
AN:
1461868
Hom.:
86
Cov.:
31
AF XY:
0.00160
AC XY:
1161
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.0681
AC:
2281
AN:
33472
Gnomad4 AMR exome
AF:
0.00425
AC:
190
AN:
44720
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26136
Gnomad4 EAS exome
AF:
0.0000504
AC:
2
AN:
39700
Gnomad4 SAS exome
AF:
0.000267
AC:
23
AN:
86258
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53416
Gnomad4 NFE exome
AF:
0.0000576
AC:
64
AN:
1112010
Gnomad4 Remaining exome
AF:
0.00500
AC:
302
AN:
60390
Heterozygous variant carriers
0
189
377
566
754
943
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
72
144
216
288
360
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0195
AC:
2968
AN:
152308
Hom.:
95
Cov.:
32
AF XY:
0.0195
AC XY:
1450
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0671
AC:
0.0671448
AN:
0.0671448
Gnomad4 AMR
AF:
0.00876
AC:
0.00875703
AN:
0.00875703
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.000207
AC:
0.000207211
AN:
0.000207211
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.000191
AC:
0.000191092
AN:
0.000191092
Gnomad4 OTH
AF:
0.0142
AC:
0.0142045
AN:
0.0142045
Heterozygous variant carriers
0
140
281
421
562
702
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
30
60
90
120
150
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00738
Hom.:
62
Bravo
AF:
0.0224
Asia WGS
AF:
0.0200
AC:
68
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:14
Revision: reviewed by expert panel
LINK: link

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

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 15, 2015
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 01, 2009
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:3
Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 21, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

RASopathy Benign:3
-
Baylor Genetics
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

Variant classified using ACMG guidelines -

Jan 31, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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.1755A>G (p.Val585=) variant in the RAF1 gene is 6.222% (690/10404) of African 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
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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
Jun 05, 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
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.56
CADD
Benign
4.9
DANN
Benign
0.80
Mutation Taster
=100/0
polymorphism (auto)

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3730296; hg19: chr3-12626394; API