rs2290159

Variant names:

• chr3-12587421-G-C
• rs2290159
• NM_002880.4:c.1417+170C>G

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.1417+170C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 716,148 control chromosomes in the GnomAD database, including 15,320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4146 hom., cov: 32)
  • Exomes 𝑓: 0.19 (11174 hom.)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0890

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-12587421-G-C is Benign according to our data. Variant chr3-12587421-G-C is described in ClinVar as [Benign]. Clinvar id is 561371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.1417+170C>G		intron_variant	Intron 13 of 16	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.1417+170C>G		intron_variant	Intron 13 of 16	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34398 AN: 151842 Hom.: 4143 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.0259

Gnomad SAS AF: 0.0993

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.219

GnomAD4 exome AF: 0.190 AC: 107105 AN: 564188 Hom.: 11174 Cov.: 6 AF XY: 0.185 AC XY: 56311 AN XY: 303918

Gnomad4 AFR exome AF: 0.297

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.0325

Gnomad4 SAS exome AF: 0.0973

Gnomad4 FIN exome AF: 0.247

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.226 AC: 34407 AN: 151960 Hom.: 4146 Cov.: 32 AF XY: 0.223 AC XY: 16528 AN XY: 74258

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.220

Gnomad4 EAS AF: 0.0256

Gnomad4 SAS AF: 0.0983

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.216

Alfa AF: 0.208 Hom.: 1870

Bravo AF: 0.226

Asia WGS AF: 0.0890 AC: 311 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.47
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2290159; hg19: chr3-12628920;