rs3729931

chr3-12585017-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002880.4(RAF1):c.1669-36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,613,362 control chromosomes in the GnomAD database, including 110,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14949 hom., cov: 31)
  • Exomes 𝑓: 0.35 (95072 hom.)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.69

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-12585017-G-A is Benign according to our data. Variant chr3-12585017-G-A is described in ClinVar as [Benign]. Clinvar id is 40624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAF1	NM_002880.4	c.1669-36C>T		intron_variant		ENST00000251849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAF1	ENST00000251849.9	c.1669-36C>T		intron_variant		1	NM_002880.4	P3

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64437 AN: 151906 Hom.: 14925 Cov.: 31

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.0528

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.406

GnomAD3 exomes AF: 0.353 AC: 88513 AN: 250924 Hom.: 17686 AF XY: 0.338 AC XY: 45801 AN XY: 135612

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.0555

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.382

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.351 AC: 513149 AN: 1461336 Hom.: 95072 Cov.: 41 AF XY: 0.344 AC XY: 250334 AN XY: 726978

Gnomad4 AFR exome AF: 0.624

Gnomad4 AMR exome AF: 0.477

Gnomad4 ASJ exome AF: 0.359

Gnomad4 EAS exome AF: 0.0626

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.386

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.424 AC: 64513 AN: 152026 Hom.: 14949 Cov.: 31 AF XY: 0.419 AC XY: 31128 AN XY: 74314

Gnomad4 AFR AF: 0.608

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.0525

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.377

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.410

Alfa AF: 0.359 Hom.: 19606

Bravo AF: 0.440

Asia WGS AF: 0.220 AC: 767 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 18, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.6
Dann	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3729931; hg19: chr3-12626516; COSMIC: COSV50109982; COSMIC: COSV50109982;