rs1532533

chr3-12594207-G-Achr3-12594207-G-T

Variant summary

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

The NM_002880.4(RAF1):c.1109-2415C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 151,796 control chromosomes in the GnomAD database, including 14,880 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 0.43 (14880 hom., cov: 30)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.854

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAF1	NM_002880.4	c.1109-2415C>T		intron_variant		ENST00000251849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAF1	ENST00000251849.9	c.1109-2415C>T		intron_variant		1	NM_002880.4	P3

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65688 AN: 151676 Hom.: 14861 Cov.: 30

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.433 AC: 65737 AN: 151796 Hom.: 14880 Cov.: 30 AF XY: 0.427 AC XY: 31646 AN XY: 74144

Gnomad4 AFR AF: 0.524

Gnomad4 AMR AF: 0.380

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.439

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.451

Alfa AF: 0.421 Hom.: 15846

Bravo AF: 0.434

Asia WGS AF: 0.237 AC: 827 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.23
Dann	Benign	0.39

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: rs1532533; hg19: chr3-12635706; COSMIC: COSV52575265; COSMIC: COSV52575265;