Genetic Variant NRG1:c.746-146360T>C (chr8-32449468-T-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.38-146360T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 151,368 control chromosomes in the GnomAD database, including 30,710 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 0.63 ( 30710 hom., cov: 31)

Consequence

NRG1
NM_001159999.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.531

Publications

11 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=-0.91).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.697 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.38-146360T>C	intron	N/A	NP_001153471.1	A0A494C1F5
NRG1	NM_001159995.3	c.38-146360T>C	intron	N/A	NP_001153467.1	A0A494C1F8
NRG1	NM_001160001.3	c.38-146360T>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.746-146360T>C	intron	N/A	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5	TSL:5	c.305-146360T>C	intron	N/A	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1		c.38-146360T>C	intron	N/A	ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.630

AC:

95257

AN:

151258

Hom.:

30686

Cov.:

show subpopulations

Gnomad AFR

AF:

0.578

Gnomad AMI

AF:

0.792

Gnomad AMR

AF:

0.708

Gnomad ASJ

AF:

0.613

Gnomad EAS

AF:

0.266

Gnomad SAS

AF:

0.569

Gnomad FIN

AF:

0.731

Gnomad MID

AF:

0.596

Gnomad NFE

AF:

0.659

Gnomad OTH

AF:

0.636

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

GnomAD4 genome

AF:

0.630

AC:

95325

AN:

151368

Hom.:

30710

Cov.:

AF XY:

0.631

AC XY:

46659

AN XY:

73984

show subpopulations

African (AFR)

AF:

0.578

AC:

23874

AN:

41324

American (AMR)

AF:

0.708

AC:

10788

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.613

AC:

2128

AN:

3470

East Asian (EAS)

AF:

0.265

AC:

1367

AN:

5156

South Asian (SAS)

AF:

0.568

AC:

2735

AN:

4816

European-Finnish (FIN)

AF:

0.731

AC:

7447

AN:

10188

Middle Eastern (MID)

AF:

0.607

AC:

176

AN:

290

European-Non Finnish (NFE)

AF:

0.659

AC:

44749

AN:

67872

Other (OTH)

AF:

0.635

AC:

1339

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1713

3426

5140

6853

8566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

778

1556

2334

3112

3890

<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:

0.647

Hom.:

133369

Bravo

AF:

0.626

Asia WGS

AF:

0.487

AC:

1689

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.9

(source)

DANN

Benign

0.71

PhyloP100

-0.53

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