rs11923427

Variant names:

• chr3-12622336-C-G
• rs11923427
• NM_002880.4:c.-26-3589G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-12622336-C-G
• chr3-12622336-C-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.-26-3589G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 152,110 control chromosomes in the GnomAD database, including 3,309 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 0.20 (3309 hom., cov: 32)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00100
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.-26-3589G>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.-26-3589G>C		intron_variant	Intron 1 of 16	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30188 AN: 151992 Hom.: 3305 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0943

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.197

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

GnomAD4 genome AF: 0.199 AC: 30198 AN: 152110 Hom.: 3309 Cov.: 32 AF XY: 0.196 AC XY: 14586 AN XY: 74348

African (AFR) AF: 0.287 AC: 11906 AN: 41480

American (AMR) AF: 0.187 AC: 2861 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 711 AN: 3472

East Asian (EAS) AF: 0.0256 AC: 133 AN: 5190

South Asian (SAS) AF: 0.0933 AC: 450 AN: 4822

European-Finnish (FIN) AF: 0.195 AC: 2055 AN: 10564

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11419 AN: 67994

Other (OTH) AF: 0.195 AC: 411 AN: 2108

Alfa AF: 0.0805 Hom.: 97

Bravo AF: 0.202

Asia WGS AF: 0.0870 AC: 303 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.4
DANN	Benign	0.62
PhyloP100		-0.0010
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: rs11923427; hg19: chr3-12663835;