3-12664356-A-G

Variant names:

• chr3-12664356-A-G
• rs3806661
• ENST00000702772.2:n.57A>G

Variant summary

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

The ENST00000702772.2(ENSG00000290072):​n.57A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 303,578 control chromosomes in the GnomAD database, including 16,441 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 0.34 (8977 hom., cov: 32)
  • Exomes 𝑓: 0.30 (7464 hom.)
• Consequence: ENSG00000290072 ENST00000702772.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 9 publications found

Genes affected

ENSG00000290072 (HGNC:):

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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.-570T>C		upstream_gene_variant		ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.-570T>C		upstream_gene_variant		1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51314 AN: 151882 Hom.: 8971 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.0308

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.332

GnomAD4 exome AF: 0.300 AC: 45472 AN: 151580 Hom.: 7464 AF XY: 0.302 AC XY: 23089 AN XY: 76508

African (AFR) AF: 0.367 AC: 1809 AN: 4930

American (AMR) AF: 0.393 AC: 1715 AN: 4360

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 2113 AN: 6114

East Asian (EAS) AF: 0.0402 AC: 560 AN: 13928

South Asian (SAS) AF: 0.169 AC: 236 AN: 1396

European-Finnish (FIN) AF: 0.347 AC: 3981 AN: 11466

Middle Eastern (MID) AF: 0.304 AC: 256 AN: 842

European-Non Finnish (NFE) AF: 0.321 AC: 31473 AN: 98124

Other (OTH) AF: 0.319 AC: 3329 AN: 10420

GnomAD4 genome AF: 0.338 AC: 51338 AN: 151998 Hom.: 8977 Cov.: 32 AF XY: 0.333 AC XY: 24752 AN XY: 74292

African (AFR) AF: 0.376 AC: 15582 AN: 41456

American (AMR) AF: 0.398 AC: 6078 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1222 AN: 3470

East Asian (EAS) AF: 0.0305 AC: 158 AN: 5176

South Asian (SAS) AF: 0.182 AC: 878 AN: 4826

European-Finnish (FIN) AF: 0.340 AC: 3591 AN: 10554

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.332 AC: 22550 AN: 67938

Other (OTH) AF: 0.329 AC: 695 AN: 2112

Alfa AF: 0.336 Hom.: 1444

Bravo AF: 0.346

Asia WGS AF: 0.134 AC: 467 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.68
PhyloP100		-1.2
PromoterAI		0.036	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3806661; hg19: chr3-12705855;