Genetic Variant NRG1:c.745+307803T>C (chr8-31948532-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.37+309101T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 152,134 control chromosomes in the GnomAD database, including 62,306 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 0.90 ( 62306 hom., cov: 31)

Consequence

NRG1
NM_001159999.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.142

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:

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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=-0.62).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.96 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.37+309101T>C	intron	N/A	NP_001153471.1	A0A494C1F5
NRG1	NM_001159995.3	c.37+309101T>C	intron	N/A	NP_001153467.1	A0A494C1F8
NRG1	NM_001160001.3	c.37+309101T>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.745+307803T>C	intron	N/A	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5	TSL:5	c.304+307803T>C	intron	N/A	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1		c.37+309101T>C	intron	N/A	ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.899

AC:

136677

AN:

152016

Hom.:

62237

Cov.:

show subpopulations

Gnomad AFR

AF:

0.967

Gnomad AMI

AF:

0.861

Gnomad AMR

AF:

0.877

Gnomad ASJ

AF:

0.889

Gnomad EAS

AF:

0.395

Gnomad SAS

AF:

0.834

Gnomad FIN

AF:

0.879

Gnomad MID

AF:

0.908

Gnomad NFE

AF:

0.909

Gnomad OTH

AF:

0.904

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

GnomAD4 genome

AF:

0.899

AC:

136807

AN:

152134

Hom.:

62306

Cov.:

AF XY:

0.894

AC XY:

66439

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.967

AC:

40168

AN:

41520

American (AMR)

AF:

0.877

AC:

13416

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.889

AC:

3085

AN:

3472

East Asian (EAS)

AF:

0.395

AC:

2024

AN:

5130

South Asian (SAS)

AF:

0.835

AC:

4012

AN:

4804

European-Finnish (FIN)

AF:

0.879

AC:

9286

AN:

10570

Middle Eastern (MID)

AF:

0.912

AC:

268

AN:

294

European-Non Finnish (NFE)

AF:

0.909

AC:

61853

AN:

68028

Other (OTH)

AF:

0.904

AC:

1910

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

629

1259

1888

2518

3147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.906

Hom.:

27975

Bravo

AF:

0.899

Asia WGS

AF:

0.689

AC:

2396

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

0.14

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