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

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_002880.4(RAF1):c.*745_*748dupAACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 233,452 control chromosomes in the GnomAD database, including 33 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.013 ( 20 hom., cov: 31)

Exomes 𝑓: 0.017 ( 13 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: -0.290

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0128 (1952/152150) while in subpopulation SAS AF= 0.018 (87/4824). AF 95% confidence interval is 0.0166. There are 20 homozygotes in gnomad4. There are 976 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 1952 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4 link	c.745_748dupAACA		3_prime_UTR_variant	17/17	ENST00000251849.9	NP_002871.1	P04049-1L7RRS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849 link	c.745_748dupAACA		3_prime_UTR_variant	17/17	1	NM_002880.4	ENSP00000251849.4		P04049-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1955

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00384

Gnomad AMI

AF:

0.0901

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.0490

Gnomad EAS

AF:

0.00405

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.00321

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0174

Gnomad OTH

AF:

0.0129

GnomAD4 exome

AF:

0.0174

AC:

1415

AN:

81302

Hom.:

Cov.:

AF XY:

0.0188

AC XY:

703

AN XY:

37434

show subpopulations

Gnomad4 AFR exome

AF:

0.00438

Gnomad4 AMR exome

AF:

0.00721

Gnomad4 ASJ exome

AF:

0.0513

Gnomad4 EAS exome

AF:

0.00493

Gnomad4 SAS exome

AF:

0.0170

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0185

Gnomad4 OTH exome

AF:

0.0167

GnomAD4 genome

AF:

0.0128

AC:

1952

AN:

152150

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

976

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00381

Gnomad4 AMR

AF:

0.0118

Gnomad4 ASJ

AF:

0.0490

Gnomad4 EAS

AF:

0.00406

Gnomad4 SAS

AF:

0.0180

Gnomad4 FIN

AF:

0.00321

Gnomad4 NFE

AF:

0.0174

Gnomad4 OTH

AF:

0.0132

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Noonan syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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