Variant 3-12583765-CTGTT-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_002880.4(RAF1):c.*745_*748delAACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0713 in 233,406 control chromosomes in the GnomAD database, including 693 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.069 ( 436 hom., cov: 31)

Exomes 𝑓: 0.075 ( 257 hom. )

Consequence

RAF1
NM_002880.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.730

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:

MKRN2 (HGNC:7113): (makorin ring finger protein 2) This gene encodes a probable E3 ubiquitin ligase containing several zinc finger domains, that is a member of the makorin RING zinc-finger protein family. This gene overlaps the v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1) gene in an antisense orientation and may have a co-regulatory function with RAF1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

MKRN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4 link	c.745_748delAACA		3_prime_UTR_variant	Exon 17 of 17	ENST00000251849.9	NP_002871.1	P04049-1L7RRS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849 link	c.745_748delAACA		3_prime_UTR_variant	Exon 17 of 17	1	NM_002880.4	ENSP00000251849.4		P04049-1

Frequencies

GnomAD3 genomes

AF:

0.0693

AC:

10529

AN:

152006

Hom.:

437

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0330

Gnomad AMI

AF:

0.135

Gnomad AMR

AF:

0.0576

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0855

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0969

Gnomad OTH

AF:

0.0707

GnomAD4 exome

AF:

0.0751

AC:

6104

AN:

81278

Hom.:

257

AF XY:

0.0760

AC XY:

2843

AN XY:

37418

show subpopulations

Gnomad4 AFR exome

AF:

0.0289

Gnomad4 AMR exome

AF:

0.0469

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.00132

Gnomad4 SAS exome

AF:

0.0227

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.0937

Gnomad4 OTH exome

AF:

0.0830

GnomAD4 genome

AF:

0.0692

AC:

10527

AN:

152128

Hom.:

436

Cov.:

AF XY:

0.0664

AC XY:

4942

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0330

Gnomad4 AMR

AF:

0.0576

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.00212

Gnomad4 SAS

AF:

0.0263

Gnomad4 FIN

AF:

0.0855

Gnomad4 NFE

AF:

0.0968

Gnomad4 OTH

AF:

0.0691

Bravo

AF:

0.0655

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome with multiple lentigines

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Noonan syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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