3-12584557-T-C

Position:

• chr3-12584557-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Moderate BS2

The NM_002880.4(RAF1):​c.1904A>G​(p.Asn635Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.84

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

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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). The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. GenCC has associacion of the 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=0.10490069).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4	c.1904A>G	p.Asn635Ser	missense_variant	17/17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.1904A>G	p.Asn635Ser	missense_variant	17/17	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251324 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2020

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 577199; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are commonly considered pathogenic (Stenson et al., 2014) -

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 635 of the RAF1 protein (p.Asn635Ser). This variant is present in population databases (rs772585174, gnomAD 0.004%). 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: 577199). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RAF1 protein function with a negative predictive value of 95%. 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	Benign	0.055
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.63
DEOGEN2	Uncertain	0.46	T;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.84	T;T;T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.011	B;.;.
Vest4		0.20
MutPred		0.21		Loss of glycosylation at T640 (P = 0.0239);.;.;
MVP		0.61
MPC		0.18
ClinPred		0.072	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.52

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: rs772585174; hg19: chr3-12626056;