Genetic Variant NRG1:c.746-395533C>T (chr8-32200295-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.38-395533C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 151,930 control chromosomes in the GnomAD database, including 17,262 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 0.45 ( 17262 hom., cov: 32)

Consequence

NRG1
NM_001159999.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.436

Publications

3 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 (AMR) allele frequency at 95% confidence interval = 0.557 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.38-395533C>T	intron	N/A	NP_001153471.1	A0A494C1F5
NRG1	NM_001159995.3	c.38-395533C>T	intron	N/A	NP_001153467.1	A0A494C1F8
NRG1	NM_001160001.3	c.38-395533C>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.746-395533C>T	intron	N/A	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5	TSL:5	c.305-395533C>T	intron	N/A	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1		c.38-395533C>T	intron	N/A	ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.454

AC:

68978

AN:

151810

Hom.:

17252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.572

Gnomad AMR

AF:

0.567

Gnomad ASJ

AF:

0.481

Gnomad EAS

AF:

0.209

Gnomad SAS

AF:

0.441

Gnomad FIN

AF:

0.567

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.550

Gnomad OTH

AF:

0.445

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

GnomAD4 genome

AF:

0.454

AC:

69012

AN:

151930

Hom.:

17262

Cov.:

AF XY:

0.456

AC XY:

33883

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.255

AC:

10562

AN:

41408

American (AMR)

AF:

0.567

AC:

8648

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.481

AC:

1668

AN:

3468

East Asian (EAS)

AF:

0.209

AC:

1081

AN:

5166

South Asian (SAS)

AF:

0.441

AC:

2128

AN:

4826

European-Finnish (FIN)

AF:

0.567

AC:

5972

AN:

10534

Middle Eastern (MID)

AF:

0.480

AC:

141

AN:

294

European-Non Finnish (NFE)

AF:

0.550

AC:

37347

AN:

67956

Other (OTH)

AF:

0.447

AC:

943

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1795

3589

5384

7178

8973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

628

1256

1884

2512

3140

<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:

0.481

Hom.:

2344

Bravo

AF:

0.446

Asia WGS

AF:

0.323

AC:

1125

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.0

(source)

DANN

Benign

0.65

PhyloP100

0.44

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