dbSNP rs1462891: NRG1:c.745+332688T>C (chr8-31973417-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+333986T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 152,074 control chromosomes in the GnomAD database, including 40,669 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 0.72 ( 40669 hom., cov: 32)

Consequence

NRG1
NM_001159999.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

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=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.814 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+333986T>C	intron	N/A	NP_001153471.1	A0A494C1F5
NRG1	NM_001159995.3	c.37+333986T>C	intron	N/A	NP_001153467.1	A0A494C1F8
NRG1	NM_001160001.3	c.37+333986T>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+332688T>C	intron	N/A	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5	TSL:5	c.304+332688T>C	intron	N/A	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1		c.37+333986T>C	intron	N/A	ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.719

AC:

109194

AN:

151956

Hom.:

40642

Cov.:

show subpopulations

Gnomad AFR

AF:

0.541

Gnomad AMI

AF:

0.819

Gnomad AMR

AF:

0.750

Gnomad ASJ

AF:

0.793

Gnomad EAS

AF:

0.386

Gnomad SAS

AF:

0.786

Gnomad FIN

AF:

0.807

Gnomad MID

AF:

0.756

Gnomad NFE

AF:

0.820

Gnomad OTH

AF:

0.737

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

GnomAD4 genome

AF:

0.719

AC:

109269

AN:

152074

Hom.:

40669

Cov.:

AF XY:

0.717

AC XY:

53321

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.541

AC:

22433

AN:

41440

American (AMR)

AF:

0.750

AC:

11473

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.793

AC:

2753

AN:

3470

East Asian (EAS)

AF:

0.386

AC:

1992

AN:

5160

South Asian (SAS)

AF:

0.787

AC:

3798

AN:

4828

European-Finnish (FIN)

AF:

0.807

AC:

8523

AN:

10564

Middle Eastern (MID)

AF:

0.769

AC:

226

AN:

294

European-Non Finnish (NFE)

AF:

0.820

AC:

55764

AN:

68006

Other (OTH)

AF:

0.740

AC:

1562

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1493

2986

4478

5971

7464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.782

Hom.:

144821

Bravo

AF:

0.702

Asia WGS

AF:

0.638

AC:

2215

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

4.1

(source)

DANN

Benign

0.47

PhyloP100

1.1

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