Variant 8-31640457-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000520407.5(NRG1):c.473C>T(p.Ala158Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,566,488 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.018 ( 92 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 72 hom. )

Consequence

NRG1
ENST00000520407.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.87

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018194616).

BP6

Variant 8-31640457-C-T is Benign according to our data. Variant chr8-31640457-C-T is described in ClinVar as [Benign]. Clinvar id is 3055726.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
NRG1	NM_013962.3 linkuse as main transcript	c.473C>T	p.Ala158Val	missense_variant	1/5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 linkuse as main transcript	c.473C>T	p.Ala158Val	missense_variant	1/13	XP_011542814.2
NRG1	XM_017013367.2 linkuse as main transcript	c.473C>T	p.Ala158Val	missense_variant	1/11	XP_016868856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
NRG1	ENST00000520407.5 linkuse as main transcript	c.473C>T	p.Ala158Val	missense_variant	1/5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5 linkuse as main transcript	c.32C>T	p.Ala11Val	missense_variant	1/13	5	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1 linkuse as main transcript	c.37+1026C>T		intron_variant			ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2804

AN:

151916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0639

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00636

Gnomad ASJ

AF:

0.00462

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.00352

AC:

646

AN:

183284

Hom.:

AF XY:

0.00272

AC XY:

278

AN XY:

102310

show subpopulations

Gnomad AFR exome

AF:

0.0661

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.00281

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000199

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.00184

AC:

2601

AN:

1414458

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1100

AN XY:

700388

show subpopulations

Gnomad4 AFR exome

AF:

0.0672

Gnomad4 AMR exome

AF:

0.00342

Gnomad4 ASJ exome

AF:

0.00323

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000271

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000514

Gnomad4 OTH exome

AF:

0.00460

GnomAD4 genome

AF:

0.0185

AC:

2810

AN:

152030

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1325

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0638

Gnomad4 AMR

AF:

0.00635

Gnomad4 ASJ

AF:

0.00462

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.0138

Alfa

AF:

0.00465

Hom.:

Bravo

AF:

0.0215

ESP6500AA

AF:

0.0618

AC:

225

ESP6500EA

AF:

0.000125

AC:

ExAC

AF:

0.00497

AC:

592

Asia WGS

AF:

0.00231

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NRG1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2019

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

-0.50

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

.;.;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.54

T;T;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;N

PROVEAN

Benign

-0.15

N;.;N

REVEL

Benign

0.16

Sift

Uncertain

0.022

D;.;D

Sift4G

Pathogenic

0.0

D;D;T

Polyphen

0.63

P;.;.

Vest4

0.11

MVP

0.45

ClinPred

0.017

GERP RS

3.8

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over