8-31640334-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_013962.3(NRG1):c.350C>T(p.Pro117Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,183,460 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0051 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 33 hom. )

Consequence

NRG1
NM_013962.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: -0.333

Publications

1 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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071258247).

BP6

Variant 8-31640334-C-T is Benign according to our data. Variant chr8-31640334-C-T is described in ClinVar as [Benign]. Clinvar id is 98388.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NRG1	NM_013962.3 link	c.350C>T	p.Pro117Leu	missense_variant	Exon 1 of 5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 link	c.350C>T	p.Pro117Leu	missense_variant	Exon 1 of 13	XP_011542814.2
NRG1	XM_017013367.2 link	c.350C>T	p.Pro117Leu	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.350C>T	p.Pro117Leu	missense_variant	Exon 1 of 5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000650866.1 link	c.37+903C>T		intron_variant	Intron 1 of 12		ENSP00000499045.1	A0A494C1F5
NRG1	ENST00000652698.1 link	c.37+903C>T		intron_variant	Intron 1 of 11		ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes

AF:

0.00511

AC:

761

AN:

148858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000463

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000934

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0488

Gnomad MID

AF:

0.00645

Gnomad NFE

AF:

0.00389

Gnomad OTH

AF:

0.00292

GnomAD2 exomes

AF:

0.0298

AC:

AN:

336

AF XY:

0.0326

show subpopulations

Gnomad FIN exome

AF:

0.0652

Gnomad NFE exome

AF:

0.00515

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00416

AC:

4306

AN:

1034500

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

1994

AN XY:

488960

show subpopulations

African (AFR)

AF:

0.000715

AC:

AN:

20982

American (AMR)

AF:

0.00147

AC:

AN:

6820

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11886

East Asian (EAS)

AF:

0.00

AC:

AN:

21996

South Asian (SAS)

AF:

0.000884

AC:

AN:

19228

European-Finnish (FIN)

AF:

0.0411

AC:

813

AN:

19784

Middle Eastern (MID)

AF:

0.00113

AC:

AN:

2648

European-Non Finnish (NFE)

AF:

0.00375

AC:

3340

AN:

891266

Other (OTH)

AF:

0.00271

AC:

108

AN:

39890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

221

442

664

885

1106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00512

AC:

762

AN:

148960

Hom.:

Cov.:

AF XY:

0.00698

AC XY:

507

AN XY:

72650

show subpopulations

African (AFR)

AF:

0.000461

AC:

AN:

41190

American (AMR)

AF:

0.000933

AC:

AN:

15002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.00

AC:

AN:

5056

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0488

AC:

459

AN:

9406

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00389

AC:

260

AN:

66792

Other (OTH)

AF:

0.00289

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00381

Hom.:

Bravo

AF:

0.00186

ExAC

AF:

0.00203

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NRG1: BP4, BS1, BS2 -

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

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.47

T;T

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.91

PhyloP100

-0.33

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.12

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.019

D;T

Polyphen

0.062

B;.

Vest4

0.18

ClinPred

0.078

GERP RS

-1.5

PromoterAI

-0.045

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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8-31640334-C-T

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