chr3-12632700-T-C

Variant names:

• chr3-12632700-T-C
• rs11709504
• NM_002880.4:c.-26-13953A>G

Variant summary

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

The NM_002880.4(RAF1):​c.-26-13953A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,120 control chromosomes in the GnomAD database, including 4,724 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 0.23 (4724 hom., cov: 32)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87
• Publications: 12 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• dilated cardiomyopathy 1NN

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

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

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

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124906355 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002880.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	NM_002880.4	MANE Select	c.-26-13953A>G		intron	N/A	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.-26-13953A>G		intron	N/A	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.-26-13953A>G		intron	N/A	NP_001341619.1	P04049-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.-26-13953A>G		intron	N/A	ENSP00000251849.4	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.-26-13953A>G		intron	N/A	ENSP00000401888.2	P04049-2
	RAF1	ENST00000900382.1		c.-26-13953A>G		intron	N/A	ENSP00000570441.1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35392 AN: 152002 Hom.: 4717 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0261

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.233 AC: 35416 AN: 152120 Hom.: 4724 Cov.: 32 AF XY: 0.229 AC XY: 17042 AN XY: 74364

African (AFR) AF: 0.364 AC: 15099 AN: 41462

American (AMR) AF: 0.203 AC: 3108 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 728 AN: 3466

East Asian (EAS) AF: 0.0258 AC: 134 AN: 5190

South Asian (SAS) AF: 0.0949 AC: 458 AN: 4826

European-Finnish (FIN) AF: 0.210 AC: 2230 AN: 10608

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

European-Non Finnish (NFE) AF: 0.190 AC: 12946 AN: 67982

Other (OTH) AF: 0.217 AC: 458 AN: 2110

Alfa AF: 0.196 Hom.: 1664

Bravo AF: 0.238

Asia WGS AF: 0.107 AC: 375 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.94
DANN	Benign	0.33
PhyloP100		-1.9
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: rs11709504; hg19: chr3-12674199;