Genetic Variant ENST00000520407.5:c.473C>A (chr8-31640457-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000520407.5(NRG1):c.473C>A(p.Ala158Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,414,458 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A158V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NRG1
ENST00000520407.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.87

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NRG1	NM_013962.3 link	c.473C>A	p.Ala158Glu	missense_variant	Exon 1 of 5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 link	c.473C>A	p.Ala158Glu	missense_variant	Exon 1 of 13	XP_011542814.2
NRG1	XM_017013367.2 link	c.473C>A	p.Ala158Glu	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.473C>A	p.Ala158Glu	missense_variant	Exon 1 of 5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5 link	c.32C>A	p.Ala11Glu	missense_variant	Exon 1 of 13	5	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1 link	c.37+1026C>A		intron_variant	Intron 1 of 12		ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000212

AC:

AN:

1414458

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700388

show subpopulations

African (AFR)

AF:

0.0000331

AC:

AN:

30190

American (AMR)

AF:

0.00

AC:

AN:

40022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24482

East Asian (EAS)

AF:

0.00

AC:

AN:

35298

South Asian (SAS)

AF:

0.00

AC:

AN:

81036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50022

Middle Eastern (MID)

AF:

0.000203

AC:

AN:

4932

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090270

Other (OTH)

AF:

0.00

AC:

AN:

58206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

.;.;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.50

T;T;T

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Benign

-0.30

PhyloP100

1.9

PROVEAN

Benign

-0.29

N;.;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.025

D;.;D

Sift4G

Pathogenic

0.0

D;D;T

Polyphen

0.99

D;.;.

Vest4

0.21

MutPred

0.62

Gain of disorder (P = 0.033);Gain of disorder (P = 0.033);.;

MVP

0.46

ClinPred

0.62

GERP RS

3.8

PromoterAI

-0.028

Neutral

(source)

Mutation Taster

=93/7

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

ENST00000520407.5:c.473C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over