rs3730297

Variant names:

• chr3-12584520-G-A
• rs3730297
• NM_002880.4:c.1941C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-12584520-G-A
• chr3-12584520-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1941C>T (p.Val647=) variant in the RAF1 gene is 1.04% (738/66732) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134718/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0070 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (86 hom.)
• Consequence: RAF1 NM_002880.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:14 O:1
• Conservation: PhyloP100: 1.18
• Publications: 13 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: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002880.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	NM_002880.4	MANE Select	c.1941C>T	p.Val647Val	synonymous	Exon 17 of 17	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.2001C>T	p.Val667Val	synonymous	Exon 18 of 18	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.1941C>T	p.Val647Val	synonymous	Exon 17 of 17	NP_001341619.1	P04049-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.1941C>T	p.Val647Val	synonymous	Exon 17 of 17	ENSP00000251849.4	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.2001C>T	p.Val667Val	synonymous	Exon 18 of 18	ENSP00000401888.2	P04049-2
	RAF1	ENST00000900382.1		c.2001C>T	p.Val667Val	synonymous	Exon 18 of 18	ENSP00000570441.1

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1070 AN: 152194 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00679 AC: 1705 AN: 251226 AF XY: 0.00671

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00726

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.00977 AC: 14286 AN: 1461886 Hom.: 86 Cov.: 31 AF XY: 0.00945 AC XY: 6873 AN XY: 727246

African (AFR) AF: 0.00102 AC: 34 AN: 33480

American (AMR) AF: 0.00445 AC: 199 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00677 AC: 177 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00180 AC: 155 AN: 86258

European-Finnish (FIN) AF: 0.00831 AC: 444 AN: 53420

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0115 AC: 12783 AN: 1112004

Other (OTH) AF: 0.00783 AC: 473 AN: 60396

GnomAD4 genome AF: 0.00703 AC: 1070 AN: 152312 Hom.: 3 Cov.: 32 AF XY: 0.00667 AC XY: 497 AN XY: 74490

African (AFR) AF: 0.00178 AC: 74 AN: 41566

American (AMR) AF: 0.0101 AC: 155 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00838 AC: 89 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 702 AN: 68034

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00878 Hom.: 9

Bravo AF: 0.00652

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0100

EpiControl AF: 0.00966

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (4)
-	-	3	RASopathy (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LEOPARD syndrome 2 (1)
-	-	1	Noonan syndrome 5 (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.3
DANN	Benign	0.58
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

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: rs3730297; hg19: chr3-12626019;