rs1129506

Positions:

• chr17-31319014-G-A
• chr17-31319014-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014210.4(EVI2A):​c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,589,844 control chromosomes in the GnomAD database, including 307,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31363 hom., cov: 31)
  • Exomes 𝑓: 0.62 (276313 hom.)
• Consequence: EVI2A NM_014210.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0580

Genes affected

EVI2A (HGNC:3499): (ecotropic viral integration site 2A) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-31319014-G-A is Benign according to our data. Variant chr17-31319014-G-A is described in ClinVar as [Benign]. Clinvar id is 403230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVI2A	NM_014210.4	c.-1C>T		5_prime_UTR_variant	2/2	ENST00000462804.3	NP_055025.2
NF1	NM_001042492.3	c.4836-6806G>A		intron_variant		ENST00000358273.9	NP_001035957.1
EVI2A	NM_001003927.3	c.69C>T	p.Ser23=	synonymous_variant	3/3		NP_001003927.1
NF1	NM_000267.3	c.4773-6806G>A		intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVI2A	ENST00000462804.3	c.-1C>T		5_prime_UTR_variant	2/2	1	NM_014210.4	ENSP00000420557	P2
NF1	ENST00000358273.9	c.4836-6806G>A		intron_variant		1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96842 AN: 151904 Hom.: 31336 Cov.: 31

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.645

GnomAD3 exomes AF: 0.590 AC: 136600 AN: 231562 Hom.: 41384 AF XY: 0.599 AC XY: 75396 AN XY: 125804

Gnomad AFR exome AF: 0.717

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.437

Gnomad SAS exome AF: 0.623

Gnomad FIN exome AF: 0.614

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.617 AC: 887360 AN: 1437822 Hom.: 276313 Cov.: 39 AF XY: 0.619 AC XY: 441941 AN XY: 714530

Gnomad4 AFR exome AF: 0.725

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.703

Gnomad4 EAS exome AF: 0.470

Gnomad4 SAS exome AF: 0.627

Gnomad4 FIN exome AF: 0.610

Gnomad4 NFE exome AF: 0.623

Gnomad4 OTH exome AF: 0.620

GnomAD4 genome AF: 0.637 AC: 96905 AN: 152022 Hom.: 31363 Cov.: 31 AF XY: 0.633 AC XY: 47016 AN XY: 74294

Gnomad4 AFR AF: 0.716

Gnomad4 AMR AF: 0.507

Gnomad4 ASJ AF: 0.702

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.620

Gnomad4 NFE AF: 0.633

Gnomad4 OTH AF: 0.641

Alfa AF: 0.624 Hom.: 49154

Bravo AF: 0.632

Asia WGS AF: 0.523 AC: 1818 AN: 3478

EpiCase AF: 0.644

EpiControl AF: 0.636

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

EVI2A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs1129506; hg19: chr17-29646032; COSMIC: COSV55986058; COSMIC: COSV55986058;