rs141791080

Variant names:

• chr3-12584631-T-C
• rs141791080
• NM_002880.4:c.1830A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-12584631-T-C
• chr3-12584631-T-A
• chr3-12584631-T-G

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.1830A>G (p.Gln610=) variant in the RAF1 gene is 0.11% (88/66740) 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/CA134712/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: RAF1 NM_002880.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:12
• Conservation: PhyloP100: -1.04
• Publications: 2 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.1830A>G	p.Gln610Gln	synonymous	Exon 17 of 17	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.1890A>G	p.Gln630Gln	synonymous	Exon 18 of 18	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.1830A>G	p.Gln610Gln	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.1830A>G	p.Gln610Gln	synonymous	Exon 17 of 17	ENSP00000251849.4	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.1890A>G	p.Gln630Gln	synonymous	Exon 18 of 18	ENSP00000401888.2	P04049-2
	RAF1	ENST00000900382.1		c.1890A>G	p.Gln630Gln	synonymous	Exon 18 of 18	ENSP00000570441.1

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 130 AN: 152126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000708 AC: 178 AN: 251386 AF XY: 0.000670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.000941

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000616 AC: 901 AN: 1461770 Hom.: 1 Cov.: 32 AF XY: 0.000627 AC XY: 456 AN XY: 727188

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 113 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.000861 AC: 46 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000626 AC: 696 AN: 1111926

Other (OTH) AF: 0.000596 AC: 36 AN: 60380

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152244 Hom.: 1 Cov.: 32 AF XY: 0.000793 AC XY: 59 AN XY: 74434

African (AFR) AF: 0.000168 AC: 7 AN: 41566

American (AMR) AF: 0.00223 AC: 34 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000808 Hom.: 0

Bravo AF: 0.00100

EpiCase AF: 0.000981

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	3	RASopathy (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LEOPARD syndrome 2 (1)
-	1	-	Noonan syndrome 5 (1)
-	-	1	RAF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.53
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs141791080; hg19: chr3-12626130; COSMIC: COSV50109287; COSMIC: COSV50109287;