8-32754452-G-T

Position:

chr8-32754452-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 1285094.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-32754452-G-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4756 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRG1	NM_013964.5 linkuse as main transcript	c.781G>T	p.Val261Leu	missense_variant	8/12	ENST00000405005.8	NP_039258.1	Q02297-1Q6PK61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8 linkuse as main transcript	c.781G>T	p.Val261Leu	missense_variant	8/12	1	NM_013964.5	ENSP00000384620.2		Q02297-1

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

GnomAD3 exomes

AF:

0.0299

AC:

7494

AN:

251018

Hom.:

159

AF XY:

0.0303

AC XY:

4104

AN XY:

135646

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 SAS exome

AF:

0.0107

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

Gnomad4 AFR exome

AF:

0.00696

Gnomad4 AMR exome

AF:

0.0284

Gnomad4 ASJ exome

AF:

0.0407

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0111

Gnomad4 FIN exome

AF:

0.0178

Gnomad4 NFE exome

AF:

0.0476

Gnomad4 OTH exome

AF:

0.0363

GnomAD4 genome

AF:

0.0312

AC:

4756

AN:

152222

Hom.:

111

Cov.:

AF XY:

0.0298

AC XY:

2218

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00934

Gnomad4 AMR

AF:

0.0362

Gnomad4 ASJ

AF:

0.0369

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.0168

Gnomad4 NFE

AF:

0.0463

Gnomad4 OTH

AF:

0.0426

Alfa

AF:

0.0438

Hom.:

245

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

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;.;T;.;.;.;.;T;.;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

.;T;T;D;T;T;T;T;D;T;D

MetaRNN

Benign

0.0051

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.7

.;.;.;.;.;L;.;L;.;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.8

N;N;N;N;.;N;.;N;N;.;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.017

D;D;D;D;.;D;.;D;D;.;D

Sift4G

Uncertain

0.034

D;D;D;D;D;D;D;D;D;D;T

Polyphen

0.96, 0.99, 0.98, 0.95

.;.;.;.;D;D;D;P;.;.;.

Vest4

0.33, 0.80, 0.77, 0.81, 0.60, 0.78, 0.76

MutPred

0.62

.;.;.;.;.;Loss of MoRF binding (P = 0.1129);.;Loss of MoRF binding (P = 0.1129);.;.;.;

MPC

0.60

ClinPred

0.037

GERP RS

5.6

Varity_R

0.38

gMVP

0.67

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