ENST00000520407.5:c.26G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000520407.5(NRG1):c.26G>A(p.Arg9His) variant causes a missense change. The variant allele was found at a frequency of 0.000458 in 1,129,492 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

NRG1
ENST00000520407.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 3.88

Publications

0 publications found

Variant links:

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

NRG1 Gene-Disease associations (from GenCC):

schizophrenia 6
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

NRG1 links:

ENSG00000302325 (HGNC:):

ENSG00000302325 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015030026).

BP6

Variant 8-31640010-G-A is Benign according to our data. Variant chr8-31640010-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 98382.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NRG1	NM_013962.3 link	c.26G>A	p.Arg9His	missense_variant	Exon 1 of 5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 link	c.26G>A	p.Arg9His	missense_variant	Exon 1 of 13	XP_011542814.2
NRG1	XM_017013367.2 link	c.26G>A	p.Arg9His	missense_variant	Exon 1 of 11	XP_016868856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
NRG1	ENST00000520407.5 link	c.26G>A	p.Arg9His	missense_variant	Exon 1 of 5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000650866.1 link	c.37+579G>A		intron_variant	Intron 1 of 12		ENSP00000499045.1	A0A494C1F5
NRG1	ENST00000652698.1 link	c.37+579G>A		intron_variant	Intron 1 of 11		ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

336

AN:

149190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00671

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000596

Gnomad OTH

AF:

0.00389

GnomAD2 exomes

AF:

0.000208

AC:

AN:

4810

AF XY:

0.000371

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000184

AC:

180

AN:

980198

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

AN XY:

462722

show subpopulations

African (AFR)

AF:

0.00722

AC:

140

AN:

19384

American (AMR)

AF:

0.00116

AC:

AN:

5178

Ashkenazi Jewish (ASJ)

AF:

0.000104

AC:

AN:

9632

East Asian (EAS)

AF:

0.00

AC:

AN:

15592

South Asian (SAS)

AF:

0.00

AC:

AN:

18706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15064

Middle Eastern (MID)

AF:

0.00151

AC:

AN:

3314

European-Non Finnish (NFE)

AF:

0.00000350

AC:

AN:

857106

Other (OTH)

AF:

0.000690

AC:

AN:

36222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00226

AC:

337

AN:

149294

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

154

AN XY:

72872

show subpopulations

African (AFR)

AF:

0.00672

AC:

277

AN:

41246

American (AMR)

AF:

0.00320

AC:

AN:

14988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000596

AC:

AN:

67122

Other (OTH)

AF:

0.00385

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00160

Hom.:

Bravo

AF:

0.00255

ExAC

AF:

0.000145

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Psychiatry Genetics Yale University

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NRG1: BP4 -

NRG1-related disorder

Benign:1

Nov 25, 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_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.028

Eigen_PC

Benign

-0.049

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.57

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.015

T;T

MetaSVM

Uncertain

-0.19

PhyloP100

3.9

PROVEAN

Benign

-0.20

N;.

REVEL

Benign

0.29

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.93

P;.

Vest4

0.14

MutPred

0.21

Loss of methylation at R9 (P = 0.0124);Loss of methylation at R9 (P = 0.0124);

MVP

0.38

ClinPred

0.23

GERP RS

3.0

PromoterAI

-0.032

Neutral

(source)

Mutation Taster

=95/5

polymorphism

(source)

Splicing

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

Publications

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ENST00000520407.5:c.26G>A

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