rs551466727

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The ENST00000251849.9(RAF1):​c.997C>T​(p.Arg333Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,612,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

RAF1
ENST00000251849.9 missense

Scores

3
8
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.27
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a region_of_interest Disordered (size 114) in uniprot entity RAF1_HUMAN there are 53 pathogenic changes around while only 18 benign (75%) in ENST00000251849.9
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RAF1. . Gene score misZ 2.4628 (greater than the threshold 3.09). Trascript score misZ 3.4185 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome 5, dilated cardiomyopathy 1NN, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome, familial isolated dilated cardiomyopathy, LEOPARD syndrome 2, Costello syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.19474441).
BS2
High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAF1NM_002880.4 linkuse as main transcriptc.997C>T p.Arg333Cys missense_variant 10/17 ENST00000251849.9 NP_002871.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAF1ENST00000251849.9 linkuse as main transcriptc.997C>T p.Arg333Cys missense_variant 10/171 NM_002880.4 ENSP00000251849 P3P04049-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000577
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251408
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1460060
Hom.:
0
Cov.:
30
AF XY:
0.0000165
AC XY:
12
AN XY:
726512
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000578
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsDec 18, 2018- -
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 333 of the RAF1 protein (p.Arg333Cys). This variant is present in population databases (rs551466727, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 411094). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAF1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Benign
-0.073
T
BayesDel_noAF
Benign
-0.12
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.;T
Eigen
Benign
-0.015
Eigen_PC
Benign
0.11
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Uncertain
0.099
D
MetaRNN
Benign
0.19
T;T;T
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
1.7
L;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-2.6
D;D;N
REVEL
Uncertain
0.42
Sift
Uncertain
0.021
D;D;D
Sift4G
Uncertain
0.035
D;D;D
Polyphen
0.015
B;.;.
Vest4
0.52
MutPred
0.46
Loss of MoRF binding (P = 0.0097);.;.;
MVP
0.88
MPC
1.6
ClinPred
0.70
D
GERP RS
4.3
Varity_R
0.34
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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: rs551466727; hg19: chr3-12641301; COSMIC: COSV52578013; COSMIC: COSV52578013; API