chr3-12654789-A-G

Position:

• chr3-12654789-A-G

Variant summary

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

The NM_002880.4(RAF1):​c.-27+9024T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0646 in 125,476 control chromosomes in the GnomAD database, including 348 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 0.065 (348 hom., cov: 26)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.468

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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4	c.-27+9024T>C		intron_variant		ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.-27+9024T>C		intron_variant		1	NM_002880.4	ENSP00000251849	P3

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 8107 AN: 125362 Hom.: 348 Cov.: 26

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00948

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.00157

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.0786

Gnomad MID AF: 0.0819

Gnomad NFE AF: 0.0944

Gnomad OTH AF: 0.0691

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

GnomAD4 genome AF: 0.0646 AC: 8104 AN: 125476 Hom.: 348 Cov.: 26 AF XY: 0.0627 AC XY: 3739 AN XY: 59614

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.0709

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.00157

Gnomad4 SAS AF: 0.0305

Gnomad4 FIN AF: 0.0786

Gnomad4 NFE AF: 0.0944

Gnomad4 OTH AF: 0.0682

Alfa AF: 0.0697 Hom.: 197

Bravo AF: 0.0508

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.75

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: rs11710163; hg19: chr3-12696288;