8-31640208-T-C

Position:

chr8-31640208-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000520407.5(NRG1):c.224T>C(p.Leu75Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,166,692 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 6 hom. )

Consequence

NRG1
ENST00000520407.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.267

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=0.014338702).

BP6

Variant 8-31640208-T-C is Benign according to our data. Variant chr8-31640208-T-C is described in ClinVar as [Benign]. Clinvar id is 3056685.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000654 (97/148254) while in subpopulation EAS AF= 0.0187 (95/5074). AF 95% confidence interval is 0.0157. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 97 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
NRG1	NM_013962.3 linkuse as main transcript	c.224T>C	p.Leu75Pro	missense_variant	1/5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 linkuse as main transcript	c.224T>C	p.Leu75Pro	missense_variant	1/13	XP_011542814.2
NRG1	XM_017013367.2 linkuse as main transcript	c.224T>C	p.Leu75Pro	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.224T>C	p.Leu75Pro	missense_variant	1/5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000650866.1 linkuse as main transcript	c.37+777T>C		intron_variant			ENSP00000499045.1	A0A494C1F5
NRG1	ENST00000652698.1 linkuse as main transcript	c.37+777T>C		intron_variant			ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes

AF:

0.000648

AC:

AN:

148146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0185

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000490

GnomAD4 exome

AF:

0.000289

AC:

294

AN:

1018438

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

124

AN XY:

482340

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0120

Gnomad4 SAS exome

AF:

0.000335

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000797

Gnomad4 OTH exome

AF:

0.000651

GnomAD4 genome

AF:

0.000654

AC:

AN:

148254

Hom.:

Cov.:

AF XY:

0.000914

AC XY:

AN XY:

72228

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0187

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000485

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00106

ExAC

AF:

0.0000647

AC:

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

Aug 07, 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

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.38

T;T

M_CAP

Pathogenic

1.0

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.47

MutationTaster

Benign

1.0

D;D

PROVEAN

Benign

-0.27

N;.

REVEL

Benign

0.14

Sift

Uncertain

0.014

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.12

B;.

Vest4

0.55

MutPred

0.31

Gain of glycosylation at L75 (P = 0.0435);Gain of glycosylation at L75 (P = 0.0435);

MVP

0.57

ClinPred

0.50

GERP RS

1.5

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