rs4684871

chr3-12655999-G-Achr3-12655999-G-Cchr3-12655999-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.-27+7814C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 150,502 control chromosomes in the GnomAD database, including 26,781 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 0.59 (26781 hom., cov: 26)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.834

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAF1	NM_002880.4	c.-27+7814C>T		intron_variant		ENST00000251849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAF1	ENST00000251849.9	c.-27+7814C>T		intron_variant		1	NM_002880.4	P3

Frequencies

GnomAD3 genomes AF: 0.590 AC: 88743 AN: 150384 Hom.: 26740 Cov.: 26

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.918

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.590 AC: 88827 AN: 150502 Hom.: 26781 Cov.: 26 AF XY: 0.597 AC XY: 43834 AN XY: 73448

Gnomad4 AFR AF: 0.514

Gnomad4 AMR AF: 0.664

Gnomad4 ASJ AF: 0.598

Gnomad4 EAS AF: 0.918

Gnomad4 SAS AF: 0.834

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.580

Gnomad4 OTH AF: 0.585

Alfa AF: 0.590 Hom.: 32043

Bravo AF: 0.593

Asia WGS AF: 0.817 AC: 2837 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	5.9
Dann	Benign	0.64

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: rs4684871; hg19: chr3-12697498;