rs5746220

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.923C>T (p.Pro308Leu) variant in the RAF1 gene is 1.516% (179/10394) 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/CA134762/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.0052 ( 6 hom., cov: 33)
Exomes 𝑓: 0.00054 ( 15 hom. )

Consequence

RAF1
NM_002880.4 missense

Scores

2
6
10

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: 6.82
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAF1NM_002880.4 linkuse as main transcriptc.923C>T p.Pro308Leu missense_variant 9/17 ENST00000251849.9 NP_002871.1 P04049-1L7RRS6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAF1ENST00000251849.9 linkuse as main transcriptc.923C>T p.Pro308Leu missense_variant 9/171 NM_002880.4 ENSP00000251849.4 P04049-1

Frequencies

GnomAD3 genomes
AF:
0.00521
AC:
793
AN:
152112
Hom.:
6
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0181
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00177
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:
0.0000441
Gnomad OTH
AF:
0.00526
GnomAD3 exomes
AF:
0.00132
AC:
332
AN:
251370
Hom.:
1
AF XY:
0.00100
AC XY:
136
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.0188
Gnomad AMR exome
AF:
0.000607
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000538
AC:
787
AN:
1461888
Hom.:
15
Cov.:
32
AF XY:
0.000479
AC XY:
348
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0194
Gnomad4 AMR exome
AF:
0.000872
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00126
GnomAD4 genome
AF:
0.00520
AC:
792
AN:
152230
Hom.:
6
Cov.:
33
AF XY:
0.00511
AC XY:
380
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.0181
Gnomad4 AMR
AF:
0.00177
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.00110
Hom.:
4
Bravo
AF:
0.00595
ESP6500AA
AF:
0.0143
AC:
63
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00156
AC:
189
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:13
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 05, 2012Pro308Leu in exon 9 of RAF1: This variant is not expected to have clinical signi ficance because it has been identified in 1.4% (54/3738) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/; dbSNP rs5746220). -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteJun 03, 2017- -
not provided Benign:4
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 08, 2022- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
RASopathy Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelApr 18, 2017The filtering allele frequency of the c.923C>T (p.Pro308Leu) variant in the RAF1 gene is 1.516% (179/10394) 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
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 01, 2018- -
Noonan syndrome 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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
AlphaMissense
Benign
0.095
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
D;.;T
Eigen
Benign
0.036
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
D;T;T
MetaRNN
Benign
0.0079
T;T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.6
L;.;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.8
D;D;D
REVEL
Uncertain
0.35
Sift
Uncertain
0.025
D;D;T
Sift4G
Benign
0.061
T;T;T
Polyphen
0.021
B;.;.
Vest4
0.38
MVP
0.39
MPC
0.47
ClinPred
0.065
T
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.22
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs5746220; hg19: chr3-12641718; API