rs3729931

Variant names:

• chr3-12585017-G-A
• rs3729931
• NM_002880.4:c.1669-36C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -1.69
• Publications: 56 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 -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 VariationId 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.

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.1669-36C>T		intron	N/A	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.1729-36C>T		intron	N/A	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.1669-36C>T		intron	N/A	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.1669-36C>T		intron	N/A	ENSP00000251849.4	P04049-1
	MKRN2	ENST00000677142.1		c.*2764G>A		3_prime_UTR	Exon 8 of 8	ENSP00000504455.1	A0A7I2V5D2
	MKRN2	ENST00000676541.1		c.*2764G>A		3_prime_UTR	Exon 8 of 8	ENSP00000503730.1	A0A7I2YQI0

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

GnomAD2 exomes AF: 0.353 AC: 88513 AN: 250924 AF XY: 0.338

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 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

African (AFR) AF: 0.624 AC: 20870 AN: 33464

American (AMR) AF: 0.477 AC: 21344 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 9371 AN: 26134

East Asian (EAS) AF: 0.0626 AC: 2485 AN: 39694

South Asian (SAS) AF: 0.202 AC: 17405 AN: 86256

European-Finnish (FIN) AF: 0.386 AC: 20571 AN: 53298

Middle Eastern (MID) AF: 0.298 AC: 1716 AN: 5768

European-Non Finnish (NFE) AF: 0.358 AC: 398174 AN: 1111646

Other (OTH) AF: 0.351 AC: 21213 AN: 60376

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

African (AFR) AF: 0.608 AC: 25195 AN: 41442

American (AMR) AF: 0.440 AC: 6716 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1237 AN: 3470

East Asian (EAS) AF: 0.0525 AC: 271 AN: 5164

South Asian (SAS) AF: 0.206 AC: 992 AN: 4824

European-Finnish (FIN) AF: 0.377 AC: 3988 AN: 10566

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24651 AN: 67968

Other (OTH) AF: 0.410 AC: 865 AN: 2108

Alfa AF: 0.374 Hom.: 45902

Bravo AF: 0.440

Asia WGS AF: 0.220 AC: 767 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.44
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3729931; hg19: chr3-12626516; COSMIC: COSV50109982; COSMIC: COSV50109982;