Genetic Variant NRG1:c.746-146138A>C (chr8-32449690-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001159999.3(NRG1):c.38-146138A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,254 control chromosomes in the GnomAD database, including 1,870 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1870 hom., cov: 32)

Consequence

NRG1
NM_001159999.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.306

Publications

7 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159999.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
NRG1	NM_001159999.3	c.38-146138A>C	intron	N/A	NP_001153471.1	A0A494C1F5
NRG1	NM_001159995.3	c.38-146138A>C	intron	N/A	NP_001153467.1	A0A494C1F8
NRG1	NM_001160001.3	c.38-146138A>C	intron	N/A	NP_001153473.1	Q02297-11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NRG1	ENST00000520407.5	TSL:1	c.746-146138A>C	intron	N/A	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5	TSL:5	c.305-146138A>C	intron	N/A	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1		c.38-146138A>C	intron	N/A	ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18480

AN:

152136

Hom.:

1868

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.0942

Gnomad EAS

AF:

0.626

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.0812

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0979

Gnomad OTH

AF:

0.119

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.122

AC:

18500

AN:

152254

Hom.:

1870

Cov.:

AF XY:

0.126

AC XY:

9366

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.106

AC:

4426

AN:

41562

American (AMR)

AF:

0.135

AC:

2065

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0942

AC:

327

AN:

3472

East Asian (EAS)

AF:

0.627

AC:

3238

AN:

5164

South Asian (SAS)

AF:

0.131

AC:

631

AN:

4828

European-Finnish (FIN)

AF:

0.0812

AC:

861

AN:

10606

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0979

AC:

6659

AN:

68020

Other (OTH)

AF:

0.116

AC:

245

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

758

1516

2273

3031

3789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.104

Hom.:

185

Bravo

AF:

0.129

Asia WGS

AF:

0.276

AC:

960

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.0

(source)

DANN

Benign

0.62

PhyloP100

-0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over