rs1532534

Variant names:

• chr3-12594756-T-G
• rs1532534
• NM_002880.4:c.1109-2964A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002880.4(RAF1):​c.1109-2964A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,180 control chromosomes in the GnomAD database, including 1,697 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 0.13 (1697 hom., cov: 31)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.632
• Publications: 13 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.1109-2964A>C		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.1109-2964A>C		intron_variant	Intron 10 of 16	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20425 AN: 152062 Hom.: 1696 Cov.: 31

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.0649

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.161

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

GnomAD4 genome AF: 0.134 AC: 20427 AN: 152180 Hom.: 1697 Cov.: 31 AF XY: 0.132 AC XY: 9819 AN XY: 74404

African (AFR) AF: 0.0407 AC: 1690 AN: 41526

American (AMR) AF: 0.113 AC: 1724 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 622 AN: 3468

East Asian (EAS) AF: 0.0563 AC: 292 AN: 5188

South Asian (SAS) AF: 0.0654 AC: 315 AN: 4820

European-Finnish (FIN) AF: 0.176 AC: 1862 AN: 10588

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13405 AN: 67992

Other (OTH) AF: 0.159 AC: 336 AN: 2110

Alfa AF: 0.166 Hom.: 1753

Bravo AF: 0.127

Asia WGS AF: 0.0680 AC: 236 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.63
PhyloP100		-0.63
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: rs1532534; hg19: chr3-12636255; COSMIC: COSV52576176;