Variant rs5746226 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.991-42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,466,904 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0095 ( 13 hom., cov: 32)

Exomes 𝑓: 0.013 ( 155 hom. )

Consequence

RAF1
NM_002880.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.59

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:

RAF1 (HGNC:):

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=-0.82).

BP6

Variant 3-12599850-A-G is Benign according to our data. Variant chr3-12599850-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 258855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00946 (1441/152318) while in subpopulation NFE AF= 0.0135 (916/68026). AF 95% confidence interval is 0.0127. There are 13 homozygotes in gnomad4. There are 660 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1441 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4 linkuse as main transcript	c.991-42T>C		intron_variant		ENST00000251849.9	NP_002871.1	P04049-1L7RRS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9 linkuse as main transcript	c.991-42T>C		intron_variant		1	NM_002880.4	ENSP00000251849.4		P04049-1

Frequencies

GnomAD3 genomes

AF:

0.00949

AC:

1444

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.0114

AC:

2863

AN:

251074

Hom.:

AF XY:

0.0117

AC XY:

1590

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0123

Gnomad FIN exome

AF:

0.00249

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0154

GnomAD4 exome

AF:

0.0130

AC:

17024

AN:

1314586

Hom.:

155

Cov.:

AF XY:

0.0130

AC XY:

8630

AN XY:

662044

show subpopulations

Gnomad4 AFR exome

AF:

0.00196

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.0321

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0121

Gnomad4 FIN exome

AF:

0.00262

Gnomad4 NFE exome

AF:

0.0141

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.00946

AC:

1441

AN:

152318

Hom.:

Cov.:

AF XY:

0.00886

AC XY:

660

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00255

Gnomad4 AMR

AF:

0.0124

Gnomad4 ASJ

AF:

0.0337

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0112

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.0135

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.00991

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Likely 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

-0.82

CADD

Benign

3.8

DANN

Benign

0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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