3-12636514-T-G

Variant names:

• chr3-12636514-T-G
• rs13060691
• NM_002880.4:c.-26-17767A>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.-26-17767A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 150,032 control chromosomes in the GnomAD database, including 1,355 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 0.12 (1355 hom., cov: 30)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.303
• Publications: 4 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.-26-17767A>C		intron_variant	Intron 1 of 16	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.-26-17767A>C		intron_variant	Intron 1 of 16	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18375 AN: 149944 Hom.: 1352 Cov.: 30

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.00473

Gnomad SAS AF: 0.0894

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0867

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.126

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

GnomAD4 genome AF: 0.123 AC: 18393 AN: 150032 Hom.: 1355 Cov.: 30 AF XY: 0.121 AC XY: 8868 AN XY: 73154

African (AFR) AF: 0.0718 AC: 2934 AN: 40836

American (AMR) AF: 0.202 AC: 3045 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 494 AN: 3464

East Asian (EAS) AF: 0.00474 AC: 24 AN: 5060

South Asian (SAS) AF: 0.0892 AC: 421 AN: 4720

European-Finnish (FIN) AF: 0.128 AC: 1290 AN: 10108

Middle Eastern (MID) AF: 0.0827 AC: 23 AN: 278

European-Non Finnish (NFE) AF: 0.142 AC: 9597 AN: 67532

Other (OTH) AF: 0.125 AC: 259 AN: 2068

Alfa AF: 0.120 Hom.: 697

Bravo AF: 0.129

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.4
DANN	Benign	0.34
PhyloP100		0.30
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: rs13060691; hg19: chr3-12678013;