3-12583765-CTGTT-C

Variant summary

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

The NM_002880.4(RAF1):c.*745_*748del 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.730

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]

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]

ACMG classification

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/exons	MANE	UniProt
RAF1	NM_002880.4	c.*745_*748del		3_prime_UTR_variant	17/17	ENST00000251849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAF1	ENST00000251849.9	c.*745_*748del		3_prime_UTR_variant	17/17	1	NM_002880.4	P3

Frequencies

GnomAD3 genomes AF: 0.0693 AC: 10529 AN: 152006 Hom.: 437 Cov.: 31

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

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.: 31 AF XY: 0.0664 AC XY: 4942 AN XY: 74406

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:2

Revision: criteria provided, single submitter

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

- -

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

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

Other links and lift over

dbSNP: rs371820097; hg19: chr3-12625264;