Genetic Variant NRG1:p.Gly46Arg (chr8-32647853-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B.

-13

BP4_StrongBP6BA1

The ENST00000520502.7(NRG1):c.136G>A(p.Gly46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,614,042 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 15 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 121 hom. )

Consequence

NRG1
ENST00000520502.7 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.53

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015679002).

BP6

Variant 8-32647853-G-A is Benign according to our data. Variant chr8-32647853-G-A is described in ClinVar as [Benign]. Clinvar id is 3060573.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5 link	c.502+30968G>A		intron_variant	Intron 5 of 11	ENST00000405005.8	NP_039258.1	Q02297-1Q6PK61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8 link	c.502+30968G>A		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2		Q02297-1

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

428

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0737

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00555

AC:

1395

AN:

251332

AF XY:

0.00484

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0731

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00229

AC:

3343

AN:

1461878

Hom.:

121

Cov.:

AF XY:

0.00219

AC XY:

1592

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0743

AC:

2950

AN:

39698

South Asian (SAS)

AF:

0.000777

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1112010

Other (OTH)

AF:

0.00475

AC:

287

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

215

430

646

861

1076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00281

AC:

428

AN:

152164

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

224

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41524

American (AMR)

AF:

0.00137

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0738

AC:

380

AN:

5146

South Asian (SAS)

AF:

0.00229

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67996

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00186

Hom.:

Bravo

AF:

0.00280

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00526

AC:

639

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NRG1-related disorder

Benign:1

Feb 18, 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

-0.66

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.77

T;.

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.1

PhyloP100

1.5

PROVEAN

Benign

-0.34

N;D

REVEL

Benign

0.060

Sift

Benign

0.41

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.0030

B;.

Vest4

0.10

MutPred

0.077

Loss of relative solvent accessibility (P = 0.0676);.;

MVP

0.093

ClinPred

0.013

GERP RS

5.2

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

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