3-12583765-C-CTGTT

Position:

• chr3-12583765-C-CTGTT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_002880.4(RAF1):​c.*748_*749insAACA 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.290

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 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	UniProt
RAF1	NM_002880.4	c.*748_*749insAACA		3_prime_UTR_variant	17/17	ENST00000251849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAF1	ENST00000251849.9	c.*748_*749insAACA		3_prime_UTR_variant	17/17	1	NM_002880.4	P3

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1955 AN: 152028 Hom.: 20 Cov.: 31

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.: 13 Cov.: 0 AF XY: 0.0188 AC XY: 703 AN XY: 37434

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.: 20 Cov.: 31 AF XY: 0.0131 AC XY: 976 AN XY: 74416

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: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

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;