rs144778786

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014210.4(EVI2A):c.527A>G(p.Gln176Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,614,056 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 20 hom. )

Consequence

EVI2A
NM_014210.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.42

Publications

11 publications found

Variant links:

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]

EVI2A links:

ENSG00000265118 (HGNC:):

ENSG00000265118 links:

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

NF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010436207).

BP6

Variant 17-31318487-T-C is Benign according to our data. Variant chr17-31318487-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVI2A	NM_014210.4 link	c.527A>G	p.Gln176Arg	missense_variant	Exon 2 of 2	ENST00000462804.3	NP_055025.2	P22794-1
NF1	NM_001042492.3 link	c.4836-7333T>C		intron_variant	Intron 36 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
EVI2A	NM_001003927.3 link	c.596A>G	p.Gln199Arg	missense_variant	Exon 3 of 3		NP_001003927.1	P22794-2
NF1	NM_000267.4 link	c.4773-7333T>C		intron_variant	Intron 35 of 56		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EVI2A	ENST00000462804.3 link	c.527A>G	p.Gln176Arg	missense_variant	Exon 2 of 2	1	NM_014210.4	ENSP00000420557.3	P22794-1
ENSG00000265118	ENST00000578584.5 link	c.299A>G	p.Gln100Arg	missense_variant	Exon 1 of 3	2		ENSP00000463981.2	J3QR06
NF1	ENST00000358273.9 link	c.4836-7333T>C		intron_variant	Intron 36 of 57	1	NM_001042492.3	ENSP00000351015.4	P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00247

AC:

376

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00442

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00246

AC:

618

AN:

250880

AF XY:

0.00244

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.000436

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00444

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00501

AC:

7324

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00487

AC XY:

3538

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33468

American (AMR)

AF:

0.000538

AC:

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86256

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00615

AC:

6843

AN:

1111972

Other (OTH)

AF:

0.00391

AC:

236

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

455

911

1366

1822

2277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00247

AC:

376

AN:

152346

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41582

American (AMR)

AF:

0.000850

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00145

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00442

AC:

301

AN:

68030

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00387

Hom.:

Bravo

AF:

0.00257

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00235

AC:

285

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EVI2A: BP4, BS2; NF1: BS2 -

Sep 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Benign:1

Apr 01, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

EVI2A-related disorder

Benign:1

Feb 11, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

.;T;.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.63

T;.;T;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.0

.;M;.;M

PhyloP100

1.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.0

.;N;N;.

REVEL

Benign

0.12

Sift

Benign

0.73

.;T;T;.

Sift4G

Benign

0.70

T;T;T;T

Polyphen

0.73, 0.86

.;P;P;P

Vest4

0.26

MVP

0.13

MPC

0.20

ClinPred

0.017

GERP RS

4.6

PromoterAI

-0.075

Neutral

(source)

Varity_R

0.12

gMVP

0.039

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over