rs80127039

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_013964.5(NRG1):c.1633C>T(p.Arg545Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0183 in 1,614,054 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R545Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.014 ( 19 hom., cov: 32)

Exomes 𝑓: 0.019 ( 287 hom. )

Consequence

NRG1
NM_013964.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:3

Conservation

PhyloP100: 5.43

Publications

19 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00954327).

BP6

Variant 8-32764112-C-T is Benign according to our data. Variant chr8-32764112-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1285009.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0137 (2081/152274) while in subpopulation NFE AF = 0.021 (1429/68028). AF 95% confidence interval is 0.0201. There are 19 homozygotes in GnomAd4. There are 967 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5 link	c.1633C>T	p.Arg545Trp	missense_variant	Exon 12 of 12	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.1633C>T	p.Arg545Trp	missense_variant	Exon 12 of 12	1	NM_013964.5	ENSP00000384620.2		Q02297-1

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2082

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00384

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.00923

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0202

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0210

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0140

AC:

3513

AN:

250966

AF XY:

0.0141

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.00845

Gnomad ASJ exome

AF:

0.0176

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0208

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0170

GnomAD4 exome

AF:

0.0188

AC:

27466

AN:

1461780

Hom.:

287

Cov.:

AF XY:

0.0184

AC XY:

13391

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00257

AC:

AN:

33480

American (AMR)

AF:

0.00944

AC:

422

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

466

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39634

South Asian (SAS)

AF:

0.00344

AC:

297

AN:

86256

European-Finnish (FIN)

AF:

0.0214

AC:

1142

AN:

53412

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0216

AC:

23967

AN:

1111980

Other (OTH)

AF:

0.0165

AC:

995

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1807

3615

5422

7230

9037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

910

1820

2730

3640

4550

<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:

0.0137

AC:

2081

AN:

152274

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

967

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00383

AC:

159

AN:

41540

American (AMR)

AF:

0.00922

AC:

141

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00269

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0202

AC:

214

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0210

AC:

1429

AN:

68028

Other (OTH)

AF:

0.0132

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

110

220

329

439

549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0183

Hom.:

100

Bravo

AF:

0.0136

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0220

AC:

189

ExAC

AF:

0.0141

AC:

1715

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0220

EpiControl

AF:

0.0203

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T;.;.;D

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D

MetaRNN

Benign

0.0095

T;T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.5

.;.;.;.;M

PhyloP100

5.4

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.5

D;D;.;.;D

REVEL

Uncertain

0.44

Sift

Benign

0.097

T;T;.;.;T

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

.;.;D;D;D

Vest4

0.32

MPC

0.84

ClinPred

0.021

GERP RS

5.8

Varity_R

0.31

gMVP

0.50

Mutation Taster

=97/3

polymorphism

(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