ENST00000520407.5:c.224T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 11/16 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

Publications

5 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 -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NRG1	NM_013962.3 link	c.224T>C	p.Leu75Pro	missense_variant	Exon 1 of 5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 link	c.224T>C	p.Leu75Pro	missense_variant	Exon 1 of 13	XP_011542814.2
NRG1	XM_017013367.2 link	c.224T>C	p.Leu75Pro	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.224T>C	p.Leu75Pro	missense_variant	Exon 1 of 5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000650866.1 link	c.37+777T>C		intron_variant	Intron 1 of 12		ENSP00000499045.1	A0A494C1F5
NRG1	ENST00000652698.1 link	c.37+777T>C		intron_variant	Intron 1 of 11		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

GnomAD2 exomes

AF:

0.00

AC:

AN:

3686

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000289

AC:

294

AN:

1018438

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

124

AN XY:

482340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20268

American (AMR)

AF:

0.00

AC:

AN:

6452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11286

East Asian (EAS)

AF:

0.0120

AC:

254

AN:

21214

South Asian (SAS)

AF:

0.000335

AC:

AN:

20878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18318

Middle Eastern (MID)

AF:

0.000346

AC:

AN:

2888

European-Non Finnish (NFE)

AF:

0.00000797

AC:

AN:

878724

Other (OTH)

AF:

0.000651

AC:

AN:

38410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000654

AC:

AN:

148254

Hom.:

Cov.:

AF XY:

0.000914

AC XY:

AN XY:

72228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41138

American (AMR)

AF:

0.00

AC:

AN:

14954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3398

East Asian (EAS)

AF:

0.0187

AC:

AN:

5074

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66408

Other (OTH)

AF:

0.000485

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Aug 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

-0.27

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

PromoterAI

-0.0028

Neutral

(source)

Mutation Taster

=84/16

polymorphism

(source)

Splicing

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

Publications

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ENST00000520407.5:c.224T>C

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