3-12663395-G-T

Variant names:

• chr3-12663395-G-T
• rs904453
• NM_002880.4:c.-27+418C>A

Variant summary

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

The NM_001354690.3(RAF1):​c.-53C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 151,984 control chromosomes in the GnomAD database, including 17,172 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 0.47 (17172 hom., cov: 32)
• Consequence: RAF1 NM_001354690.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138
• Publications: 16 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• 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_001354690.3. 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+418C>A		intron	N/A	NP_002871.1	L7RRS6
	RAF1	NM_001354690.3		c.-53C>A		5_prime_UTR	Exon 1 of 17	NP_001341619.1	P04049-1
	RAF1	NM_001354689.3		c.-27+418C>A		intron	N/A	NP_001341618.1	A0A0S2Z559

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.-27+418C>A		intron	N/A	ENSP00000251849.4	P04049-1
	RAF1	ENST00000900382.1		c.-53C>A		5_prime_UTR	Exon 1 of 18	ENSP00000570441.1
	RAF1	ENST00000691899.1		c.-53C>A		5_prime_UTR	Exon 1 of 17	ENSP00000508763.1	P04049-1

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70622 AN: 151866 Hom.: 17143 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.465 AC: 70693 AN: 151984 Hom.: 17172 Cov.: 32 AF XY: 0.473 AC XY: 35151 AN XY: 74288

African (AFR) AF: 0.434 AC: 17995 AN: 41440

American (AMR) AF: 0.462 AC: 7046 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1580 AN: 3470

East Asian (EAS) AF: 0.911 AC: 4696 AN: 5154

South Asian (SAS) AF: 0.748 AC: 3606 AN: 4822

European-Finnish (FIN) AF: 0.439 AC: 4639 AN: 10564

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

European-Non Finnish (NFE) AF: 0.438 AC: 29747 AN: 67960

Other (OTH) AF: 0.458 AC: 965 AN: 2106

Alfa AF: 0.431 Hom.: 7187

Bravo AF: 0.462

Asia WGS AF: 0.770 AC: 2674 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.8
DANN	Benign	0.72
PhyloP100		0.14
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs904453; hg19: chr3-12704894;