Variant summary

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

The NM_013964.5(NRG1):c.781G>T(p.Val261Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.04 in 1,613,700 control chromosomes in the GnomAD database, including 1,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.031 ( 111 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1407 hom. )

Consequence

NRG1
NM_013964.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:3

Conservation

PhyloP100: 10.0

Publications

36 publications found

Variant links:

COSMIC-nc: COSV104382605

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=0.0050670207).

BP6

Variant 8-32754452-G-T is Benign according to our data. Variant chr8-32754452-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1285094.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0312 (4756/152222) while in subpopulation NFE AF = 0.0463 (3150/68018). AF 95% confidence interval is 0.045. There are 111 homozygotes in GnomAd4. There are 2218 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 111 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013964.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRG1	NM_013964.5	MANE Select	c.781G>T	p.Val261Leu	missense	Exon 8 of 12	NP_039258.1
NRG1	NM_001322205.2		c.961G>T	p.Val321Leu	missense	Exon 5 of 9	NP_001309134.1
NRG1	NM_013956.5		c.796G>T	p.Val266Leu	missense	Exon 9 of 13	NP_039250.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRG1	ENST00000405005.8	TSL:1 MANE Select	c.781G>T	p.Val261Leu	missense	Exon 8 of 12	ENSP00000384620.2
NRG1	ENST00000287842.7	TSL:1	c.796G>T	p.Val266Leu	missense	Exon 9 of 13	ENSP00000287842.4
NRG1	ENST00000356819.7	TSL:1	c.772G>T	p.Val258Leu	missense	Exon 8 of 12	ENSP00000349275.6

Frequencies

GnomAD3 genomes

AF:

0.0313

AC:

4757

AN:

152104

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00937

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.0362

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0463

Gnomad OTH

AF:

0.0435

GnomAD2 exomes

AF:

0.0299

AC:

7494

AN:

251018

AF XY:

0.0303

show subpopulations

Gnomad AFR exome

AF:

0.00838

Gnomad AMR exome

AF:

0.0278

Gnomad ASJ exome

AF:

0.0410

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0168

Gnomad NFE exome

AF:

0.0446

Gnomad OTH exome

AF:

0.0369

GnomAD4 exome

AF:

0.0409

AC:

59771

AN:

1461478

Hom.:

1407

Cov.:

AF XY:

0.0402

AC XY:

29191

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.00696

AC:

233

AN:

33468

American (AMR)

AF:

0.0284

AC:

1270

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0407

AC:

1062

AN:

26124

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39668

South Asian (SAS)

AF:

0.0111

AC:

959

AN:

86234

European-Finnish (FIN)

AF:

0.0178

AC:

950

AN:

53404

Middle Eastern (MID)

AF:

0.0295

AC:

170

AN:

5764

European-Non Finnish (NFE)

AF:

0.0476

AC:

52932

AN:

1111752

Other (OTH)

AF:

0.0363

AC:

2192

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2953

5907

8860

11814

14767

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1980

3960

5940

7920

9900

<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:

0.0312

AC:

4756

AN:

152222

Hom.:

111

Cov.:

AF XY:

0.0298

AC XY:

2218

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00934

AC:

388

AN:

41538

American (AMR)

AF:

0.0362

AC:

553

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

128

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0106

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0168

AC:

178

AN:

10608

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0463

AC:

3150

AN:

68018

Other (OTH)

AF:

0.0426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

241

483

724

966

1207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0421

Hom.:

491

Bravo

AF:

0.0334

TwinsUK

AF:

0.0502

AC:

186

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.0471

AC:

405

ExAC

AF:

0.0285

AC:

3463

Asia WGS

AF:

0.00549

AC:

AN:

3476

EpiCase

AF:

0.0517

EpiControl

AF:

0.0512

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.7

PhyloP100

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.37

Sift

Uncertain

0.017

Sift4G

Uncertain

0.034

Polyphen

0.96

Vest4

0.33

MutPred

0.62

Loss of MoRF binding (P = 0.1129)

MPC

0.60

ClinPred

0.037

GERP RS

5.6

Varity_R

0.38

gMVP

0.67

Mutation Taster

=30/70

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over