Variant rs34918173 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001322205.2(NRG1):c.101C>A(p.Ala34Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,613,906 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.013 ( 40 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 44 hom. )

Consequence

NRG1
NM_001322205.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.43

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:

NRG1 (HGNC:):

NRG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a site Breakpoint for translocation to form gamma-heregulin (size 0) in uniprot entity NRG1_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0020082295).

BP6

Variant 8-32647818-C-A is Benign according to our data. Variant chr8-32647818-C-A is described in ClinVar as [Benign]. Clinvar id is 3038833.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1964/152064) while in subpopulation AFR AF= 0.0449 (1863/41476). AF 95% confidence interval is 0.0432. There are 40 homozygotes in gnomad4. There are 915 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1964 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRG1	NM_013964.5 linkuse as main transcript	c.502+30933C>A		intron_variant		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.502+30933C>A		intron_variant		1	NM_013964.5	ENSP00000384620.2		Q02297-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1957

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00357

AC:

896

AN:

251214

Hom.:

AF XY:

0.00275

AC XY:

374

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.0473

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00136

AC:

1995

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

877

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0472

Gnomad4 AMR exome

AF:

0.00282

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000665

Gnomad4 OTH exome

AF:

0.00301

GnomAD4 genome

AF:

0.0129

AC:

1964

AN:

152064

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

915

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0449

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00247

Hom.:

Bravo

AF:

0.0144

ESP6500AA

AF:

0.0443

AC:

195

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00446

AC:

541

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

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

Apr 16, 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

-0.57

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.061

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.11

REVEL

Benign

0.038

Sift

Benign

0.091

Sift4G

Benign

0.11

Polyphen

0.23

Vest4

0.33

MVP

0.34

ClinPred

0.0062

GERP RS

5.2

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