Genetic Variant NRG1:p.Val133Leu (chr8-32648114-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000520502.7(NRG1):c.397G>C(p.Val133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,614,138 control chromosomes in the GnomAD database, including 634 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 70 hom., cov: 32)

Exomes 𝑓: 0.018 ( 564 hom. )

Consequence

NRG1
ENST00000520502.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.83

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017232895).

BP6

Variant 8-32648114-G-C is Benign according to our data. Variant chr8-32648114-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 218702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5 link	c.502+31229G>C		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+31229G>C		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2		Q02297-1

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

3636

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0338

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0283

Gnomad ASJ

AF:

0.0438

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0611

Gnomad FIN

AF:

0.00462

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0502

GnomAD2 exomes

AF:

0.0244

AC:

6142

AN:

251484

AF XY:

0.0267

show subpopulations

Gnomad AFR exome

AF:

0.0328

Gnomad AMR exome

AF:

0.0248

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.00360

Gnomad NFE exome

AF:

0.0184

Gnomad OTH exome

AF:

0.0358

GnomAD4 exome

AF:

0.0184

AC:

26885

AN:

1461886

Hom.:

564

Cov.:

AF XY:

0.0201

AC XY:

14631

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0377

AC:

1262

AN:

33480

American (AMR)

AF:

0.0254

AC:

1135

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0382

AC:

999

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.0621

AC:

5360

AN:

86258

European-Finnish (FIN)

AF:

0.00356

AC:

190

AN:

53414

Middle Eastern (MID)

AF:

0.114

AC:

657

AN:

5768

European-Non Finnish (NFE)

AF:

0.0141

AC:

15678

AN:

1112010

Other (OTH)

AF:

0.0264

AC:

1593

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1797

3594

5390

7187

8984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

588

1176

1764

2352

2940

<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:

0.0238

AC:

3630

AN:

152252

Hom.:

Cov.:

AF XY:

0.0243

AC XY:

1807

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0337

AC:

1400

AN:

41540

American (AMR)

AF:

0.0282

AC:

431

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0438

AC:

152

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0605

AC:

291

AN:

4810

European-Finnish (FIN)

AF:

0.00462

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1168

AN:

68022

Other (OTH)

AF:

0.0497

AC:

105

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

164

328

493

657

821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0199

Hom.:

Bravo

AF:

0.0253

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.0245

AC:

108

ESP6500EA

AF:

0.0186

AC:

160

ExAC

AF:

0.0249

AC:

3022

Asia WGS

AF:

0.0330

AC:

114

AN:

3478

EpiCase

AF:

0.0245

EpiControl

AF:

0.0264

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 06, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.19

Eigen_PC

Benign

0.0070

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.54

T;.

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

PhyloP100

1.8

PROVEAN

Benign

0.26

N;N

REVEL

Benign

0.024

Sift

Benign

0.10

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.012

B;.

Vest4

0.050

MutPred

0.17

Gain of sheet (P = 0.0477);.;

ClinPred

0.0051

GERP RS

4.3

Mutation Taster

=89/11

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