rs1532533

Variant names:

• chr3-12594207-G-A
• rs1532533
• NM_002880.4:c.1109-2415C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-12594207-G-A
• chr3-12594207-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 publications found

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]

RAF1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P
• dilated cardiomyopathy 1NN

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• LEOPARD syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.1109-2415C>T		intron_variant	Intron 10 of 16	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.1109-2415C>T		intron_variant	Intron 10 of 16	1	NM_002880.4	ENSP00000251849.4

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

African (AFR) AF: 0.524 AC: 21656 AN: 41360

American (AMR) AF: 0.380 AC: 5791 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1416 AN: 3472

East Asian (EAS) AF: 0.105 AC: 540 AN: 5158

South Asian (SAS) AF: 0.184 AC: 887 AN: 4812

European-Finnish (FIN) AF: 0.439 AC: 4614 AN: 10502

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29424 AN: 67954

Other (OTH) AF: 0.451 AC: 949 AN: 2106

Alfa AF: 0.425 Hom.: 20237

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
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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