Genetic Variant NRG1:c.746-236119C>T (chr8-32359709-C-T) – 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.38-236119C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 151,954 control chromosomes in the GnomAD database, including 21,719 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 0.53 ( 21719 hom., cov: 33)

Consequence

NRG1
NM_001159999.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0130

Publications

6 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:

Genome browser will be placed here

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=-0.51).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.725 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.38-236119C>T	intron	N/A	NP_001153471.1	A0A494C1F5
NRG1	NM_001159995.3	c.38-236119C>T	intron	N/A	NP_001153467.1	A0A494C1F8
NRG1	NM_001160001.3	c.38-236119C>T	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.746-236119C>T	intron	N/A	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5	TSL:5	c.305-236119C>T	intron	N/A	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1		c.38-236119C>T	intron	N/A	ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.530

AC:

80431

AN:

151836

Hom.:

21687

Cov.:

show subpopulations

Gnomad AFR

AF:

0.601

Gnomad AMI

AF:

0.514

Gnomad AMR

AF:

0.489

Gnomad ASJ

AF:

0.480

Gnomad EAS

AF:

0.745

Gnomad SAS

AF:

0.532

Gnomad FIN

AF:

0.490

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.489

Gnomad OTH

AF:

0.499

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

GnomAD4 genome

AF:

0.530

AC:

80515

AN:

151954

Hom.:

21719

Cov.:

AF XY:

0.532

AC XY:

39491

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.601

AC:

24907

AN:

41440

American (AMR)

AF:

0.490

AC:

7478

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.480

AC:

1666

AN:

3468

East Asian (EAS)

AF:

0.745

AC:

3851

AN:

5170

South Asian (SAS)

AF:

0.532

AC:

2568

AN:

4828

European-Finnish (FIN)

AF:

0.490

AC:

5156

AN:

10528

Middle Eastern (MID)

AF:

0.490

AC:

144

AN:

294

European-Non Finnish (NFE)

AF:

0.489

AC:

33231

AN:

67934

Other (OTH)

AF:

0.495

AC:

1046

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1970

3939

5909

7878

9848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

714

1428

2142

2856

3570

<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:

0.493

Hom.:

24508

Bravo

AF:

0.531

Asia WGS

AF:

0.603

AC:

2100

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.013

Mutation Taster

=100/0

polymorphism (auto)

(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.

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