Genetic Variant ENST00000520407.5:c.11G>C (chr8-31639995-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000520407.5(NRG1):c.11G>C(p.Arg4Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000448 in 1,124,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

NRG1
ENST00000520407.5 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 3.58

Publications

3 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021544874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NRG1	NM_013962.3 link	c.11G>C	p.Arg4Pro	missense_variant	Exon 1 of 5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 link	c.11G>C	p.Arg4Pro	missense_variant	Exon 1 of 13	XP_011542814.2
NRG1	XM_017013367.2 link	c.11G>C	p.Arg4Pro	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.11G>C	p.Arg4Pro	missense_variant	Exon 1 of 5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000650866.1 link	c.37+564G>C		intron_variant	Intron 1 of 12		ENSP00000499045.1	A0A494C1F5
NRG1	ENST00000652698.1 link	c.37+564G>C		intron_variant	Intron 1 of 11		ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes

AF:

0.000548

AC:

AN:

149538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000729

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000932

Gnomad ASJ

AF:

0.00348

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000729

Gnomad OTH

AF:

0.000486

GnomAD2 exomes

AF:

0.00116

AC:

AN:

6882

AF XY:

0.000834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00617

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00110

Gnomad OTH exome

AF:

0.00725

GnomAD4 exome

AF:

0.000432

AC:

421

AN:

975198

Hom.:

Cov.:

AF XY:

0.000452

AC XY:

208

AN XY:

459736

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19260

American (AMR)

AF:

0.000397

AC:

AN:

5034

Ashkenazi Jewish (ASJ)

AF:

0.00336

AC:

AN:

9518

East Asian (EAS)

AF:

0.00

AC:

AN:

15268

South Asian (SAS)

AF:

0.000107

AC:

AN:

18636

European-Finnish (FIN)

AF:

0.0000675

AC:

AN:

14810

Middle Eastern (MID)

AF:

0.00425

AC:

AN:

3528

European-Non Finnish (NFE)

AF:

0.000404

AC:

345

AN:

853174

Other (OTH)

AF:

0.000667

AC:

AN:

35970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000555

AC:

AN:

149644

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

AN XY:

73052

show subpopulations

African (AFR)

AF:

0.0000727

AC:

AN:

41250

American (AMR)

AF:

0.000931

AC:

AN:

15038

Ashkenazi Jewish (ASJ)

AF:

0.00348

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9434

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000729

AC:

AN:

67234

Other (OTH)

AF:

0.000962

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000532

Hom.:

Bravo

AF:

0.000680

ExAC

AF:

0.000108

AC:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

Psychiatry Genetics Yale University

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

0.064

Eigen_PC

Benign

0.047

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.47

T;T

M_CAP

Pathogenic

1.0

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-0.64

PhyloP100

3.6

PROVEAN

Benign

0.79

N;.

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.90

P;.

Vest4

0.53

MVP

0.44

ClinPred

0.24

GERP RS

2.0

PromoterAI

-0.14

Neutral

(source)

Mutation Taster

=91/9

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.11G>C

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