rs6795441

Variant names:

• chr3-12661063-A-G
• rs6795441
• NM_002880.4:c.-27+2750T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-12661063-A-G
• chr3-12661063-A-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.-27+2750T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 152,036 control chromosomes in the GnomAD database, including 17,264 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. The gene RAF1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.47 (17264 hom., cov: 33)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 8 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

ACMG classification

Specifications for RAF1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.889 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.-27+2750T>C		intron	N/A	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.-27+2750T>C		intron	N/A	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.-27+2306T>C		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.-27+2750T>C		intron	N/A	ENSP00000251849.4	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.-27+2750T>C		intron	N/A	ENSP00000401888.2	P04049-2
	RAF1	ENST00000900382.1		c.-27+2306T>C		intron	N/A	ENSP00000570441.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70872 AN: 151918 Hom.: 17240 Cov.: 33

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.459

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

GnomAD4 genome AF: 0.467 AC: 70941 AN: 152036 Hom.: 17264 Cov.: 33 AF XY: 0.475 AC XY: 35275 AN XY: 74316

African (AFR) AF: 0.438 AC: 18173 AN: 41454

American (AMR) AF: 0.463 AC: 7066 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1582 AN: 3468

East Asian (EAS) AF: 0.911 AC: 4723 AN: 5184

South Asian (SAS) AF: 0.747 AC: 3602 AN: 4820

European-Finnish (FIN) AF: 0.438 AC: 4627 AN: 10556

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29778 AN: 67962

Other (OTH) AF: 0.460 AC: 972 AN: 2112

Alfa AF: 0.447 Hom.: 18527

Bravo AF: 0.463

Asia WGS AF: 0.770 AC: 2673 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.91
PhyloP100		2.2
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: rs6795441; hg19: chr3-12702562;