rs368796800

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PP2BP6_StrongBS2

The NM_002880.4(RAF1):​c.835G>A​(p.Asp279Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

RAF1
NM_002880.4 missense, splice_region

Scores

1
7
11
Splicing: ADA: 0.9976
2

Clinical Significance

Uncertain significance reviewed by expert panel U:3B:2

Conservation

PhyloP100: 3.46
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 Likely_benign. Variant got -5 ACMG points.

PM1
In a region_of_interest Disordered (size 114) in uniprot entity RAF1_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_002880.4
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.
BP6
Variant 3-12600415-C-T is Benign according to our data. Variant chr3-12600415-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 181510.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAF1NM_002880.4 linkuse as main transcriptc.835G>A p.Asp279Asn missense_variant, splice_region_variant 8/17 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.835G>A p.Asp279Asn missense_variant, splice_region_variant 8/171 NM_002880.4 ENSP00000251849.4 P04049-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152116
Hom.:
0
Cov.:
33
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:
0.000769
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251426
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000381
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461852
Hom.:
0
Cov.:
32
AF XY:
0.0000206
AC XY:
15
AN XY:
727224
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:
0.000151
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152234
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000771
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3Benign:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

RASopathy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 04, 2024This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 279 of the RAF1 protein (p.Asp279Asn). This variant is present in population databases (rs368796800, gnomAD 0.03%). 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: 181510). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
Uncertain significance, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelSep 24, 2019The c.835G>A (p.Asp279Asn) variant in RAF1 has been identified in 0.01786% (lower bound of the 95% CI of 7/18394) of East Asian chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been observed in several individuals with varying clinical presentations that lack clear associations with a RASopathy. It was also seen in 13 individuals clinically unaffected with a RASopathy (BS2; GeneDx internal data). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS2. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 22, 2021The p.D279N variant (also known as c.835G>A), located in coding exon 7 of the RAF1 gene, results from a G to A substitution at nucleotide position 835. This variant impacts the first base pair of coding exon 7. The aspartic acid at codon 279 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 01, 2024Variant summary: RAF1 c.835G>A (p.Asp279Asn) alters a conserved nucleotide located at the exon-intron boundary of the RAF1 gene resulting in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools via ALAMUT predict no significant impact on normal splicing. Another in-silico tool for assessing the pathogenicity of synonymous variants, namely TraP (Transcript-inferred Pathogenicity, Gelfman_2017) predicts this variant to be benign. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251426 control chromosomes (gnomAD). The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.835G>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 181510). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 09, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.23
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D;.;T
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;T;D
M_CAP
Benign
0.085
D
MetaRNN
Benign
0.085
T;T;T
MetaSVM
Benign
-0.40
T
MutationAssessor
Uncertain
2.6
M;.;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Benign
0.24
Sift
Benign
0.12
T;T;T
Sift4G
Benign
0.24
T;T;T
Polyphen
0.41
B;.;.
Vest4
0.58
MutPred
0.20
Gain of glycosylation at S283 (P = 0.0075);.;.;
MVP
0.80
MPC
0.46
ClinPred
0.086
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.12
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.81
SpliceAI score (max)
0.050
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: rs368796800; hg19: chr3-12641914; API