Variant chr3-12591669-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002880.4(RAF1):c.1193+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,557,200 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 32 hom., cov: 32)

Exomes 𝑓: 0.014 ( 181 hom. )

Consequence

RAF1
NM_002880.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.948

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 3-12591669-A-G is Benign according to our data. Variant chr3-12591669-A-G is described in ClinVar as [Benign]. Clinvar id is 258851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-12591669-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0146 (2228/152288) while in subpopulation AMR AF= 0.0445 (680/15294). AF 95% confidence interval is 0.0417. There are 32 homozygotes in gnomad4. There are 1153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAF1	NM_002880.4 linkuse as main transcript	c.1193+39T>C		intron_variant		ENST00000251849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAF1	ENST00000251849.9 linkuse as main transcript	c.1193+39T>C		intron_variant		1	NM_002880.4	P3	P04049-1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2218

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00582

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0445

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.0278

GnomAD3 exomes

AF:

0.0170

AC:

4274

AN:

250920

Hom.:

AF XY:

0.0164

AC XY:

2219

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.00480

Gnomad AMR exome

AF:

0.0369

Gnomad ASJ exome

AF:

0.00398

Gnomad EAS exome

AF:

0.0277

Gnomad SAS exome

AF:

0.0161

Gnomad FIN exome

AF:

0.00950

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0136

AC:

19070

AN:

1404912

Hom.:

181

Cov.:

AF XY:

0.0134

AC XY:

9405

AN XY:

702318

show subpopulations

Gnomad4 AFR exome

AF:

0.00543

Gnomad4 AMR exome

AF:

0.0388

Gnomad4 ASJ exome

AF:

0.00337

Gnomad4 EAS exome

AF:

0.0261

Gnomad4 SAS exome

AF:

0.0157

Gnomad4 FIN exome

AF:

0.0102

Gnomad4 NFE exome

AF:

0.0125

Gnomad4 OTH exome

AF:

0.0141

GnomAD4 genome

AF:

0.0146

AC:

2228

AN:

152288

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1153

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00582

Gnomad4 AMR

AF:

0.0445

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.0230

Gnomad4 SAS

AF:

0.0180

Gnomad4 FIN

AF:

0.0106

Gnomad4 NFE

AF:

0.0133

Gnomad4 OTH

AF:

0.0318

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.0165

Asia WGS

AF:

0.0510

AC:

178

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.34

DANN

Benign

0.25

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over