3-12632700-T-C

Position:

• chr3-12632700-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002880.4(RAF1):​c.-26-13953A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,120 control chromosomes in the GnomAD database, including 4,724 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4724 hom., cov: 32)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87

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]

LOC124906355 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4	c.-26-13953A>G		intron_variant		ENST00000251849.9	NP_002871.1
LOC124906355	XR_007096323.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.-26-13953A>G		intron_variant		1	NM_002880.4	ENSP00000251849	P3

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35392 AN: 152002 Hom.: 4717 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0261

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.216

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.233 AC: 35416 AN: 152120 Hom.: 4724 Cov.: 32 AF XY: 0.229 AC XY: 17042 AN XY: 74364

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.203

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.0258

Gnomad4 SAS AF: 0.0949

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.217

Alfa AF: 0.193 Hom.: 1432

Bravo AF: 0.238

Asia WGS AF: 0.107 AC: 375 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.94
DANN	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs11709504; hg19: chr3-12674199;