NM_014210.4:c.-1C>T

Variant names:

• chr17-31319014-G-A
• rs1129506
• NM_014210.4:c.-1C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 39 publications found

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]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000265118 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
EVI2A	NM_014210.4	c.-1C>T		5_prime_UTR_variant	Exon 2 of 2	ENST00000462804.3	NP_055025.2
NF1	NM_001042492.3	c.4836-6806G>A		intron_variant	Intron 36 of 57	ENST00000358273.9	NP_001035957.1
EVI2A	NM_001003927.3	c.69C>T	p.Ser23Ser	synonymous_variant	Exon 3 of 3		NP_001003927.1
NF1	NM_000267.4	c.4773-6806G>A		intron_variant	Intron 35 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVI2A	ENST00000462804.3	c.-1C>T		5_prime_UTR_variant	Exon 2 of 2	1	NM_014210.4	ENSP00000420557.3
NF1	ENST00000358273.9	c.4836-6806G>A		intron_variant	Intron 36 of 57	1	NM_001042492.3	ENSP00000351015.4
ENSG00000265118	ENST00000578584.5	c.-229C>T		upstream_gene_variant		2		ENSP00000463981.2

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

GnomAD2 exomes AF: 0.590 AC: 136600 AN: 231562 AF XY: 0.599

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 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

African (AFR) AF: 0.725 AC: 23494 AN: 32418

American (AMR) AF: 0.425 AC: 17263 AN: 40634

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 17659 AN: 25114

East Asian (EAS) AF: 0.470 AC: 18568 AN: 39516

South Asian (SAS) AF: 0.627 AC: 52520 AN: 83748

European-Finnish (FIN) AF: 0.610 AC: 29106 AN: 47736

Middle Eastern (MID) AF: 0.713 AC: 4034 AN: 5660

European-Non Finnish (NFE) AF: 0.623 AC: 687822 AN: 1103482

Other (OTH) AF: 0.620 AC: 36894 AN: 59514

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

African (AFR) AF: 0.716 AC: 29701 AN: 41474

American (AMR) AF: 0.507 AC: 7747 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2438 AN: 3472

East Asian (EAS) AF: 0.444 AC: 2289 AN: 5160

South Asian (SAS) AF: 0.618 AC: 2978 AN: 4816

European-Finnish (FIN) AF: 0.620 AC: 6548 AN: 10554

Middle Eastern (MID) AF: 0.671 AC: 196 AN: 292

European-Non Finnish (NFE) AF: 0.633 AC: 43019 AN: 67956

Other (OTH) AF: 0.641 AC: 1356 AN: 2116

Alfa AF: 0.629 Hom.: 83507

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

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

EVI2A-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.058
PromoterAI		-0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

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