3-12584624-G-T

Variant names:

• chr3-12584624-G-T
• rs80338797
• NM_002880.4:c.1837C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_002880.4(RAF1):​c.1837C>A​(p.Leu613Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L613V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.76
• Publications: 65 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_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_002880.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-12584624-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13960.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP5: Variant 3-12584624-G-T is Pathogenic according to our data. Variant chr3-12584624-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521674.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.1837C>A	p.Leu613Ile	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.1837C>A	p.Leu613Ile	missense_variant	Exon 17 of 17	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

May 31, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.094	D
MutationAssessor	Uncertain	2.8	M;.;.
PhyloP100		3.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.46	P;.;.
Vest4		0.47
MutPred		0.76		Loss of catalytic residue at L613 (P = 0.0215);.;.;
MVP		0.75
MPC		0.57
ClinPred		0.97	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.53
gMVP		0.65
Mutation Taster		=40/60	disease causing (ClinVar)

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: rs80338797; hg19: chr3-12626123;