3-12584539-G-C

Variant names:

• chr3-12584539-G-C
• rs587777587
• NM_002880.4:c.1922C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM5 BS2

The NM_002880.4(RAF1):​c.1922C>G​(p.Thr641Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T641M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.46
• Publications: 8 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-12584539-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142298.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.1922C>G	p.Thr641Arg	missense_variant	Exon 17 of 17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.1922C>G	p.Thr641Arg	missense_variant	Exon 17 of 17	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251256 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112012

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T641R variant (also known as c.1922C>G), located in coding exon 16 of the RAF1 gene, results from a C to G substitution at nucleotide position 1922. The threonine at codon 641 is replaced by arginine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

LEOPARD syndrome 2;C1969057:Noonan syndrome 5 Uncertain:1

Jul 30, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Uncertain	-0.085	T
MutationAssessor	Benign	0.97	L;.;.
PhyloP100		6.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0070	D;D;D
Sift4G	Benign	0.20	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.67
MutPred		0.26		Loss of glycosylation at T640 (P = 0.0239);.;.;
MVP		0.87
MPC		0.73
ClinPred		0.66	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.59
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs587777587; hg19: chr3-12626038;