Genetic Variant NRG1:c.746-53489C>T (chr8-32542339-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.38-53489C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,042 control chromosomes in the GnomAD database, including 2,115 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 0.11 ( 2115 hom., cov: 33)

Consequence

NRG1
NM_001159999.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.378

Publications

2 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 (EAS) allele frequency at 95% confidence interval = 0.565 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.38-53489C>T	intron	N/A	NP_001153471.1	A0A494C1F5
NRG1	NM_001159995.3	c.38-53489C>T	intron	N/A	NP_001153467.1	A0A494C1F8
NRG1	NM_001160001.3	c.38-53489C>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.746-53489C>T	intron	N/A	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5	TSL:5	c.305-53489C>T	intron	N/A	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1		c.38-53489C>T	intron	N/A	ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15931

AN:

151924

Hom.:

2101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0871

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.581

Gnomad SAS

AF:

0.0978

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.0903

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

GnomAD4 genome

AF:

0.105

AC:

15970

AN:

152042

Hom.:

2115

Cov.:

AF XY:

0.107

AC XY:

7980

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.228

AC:

9443

AN:

41416

American (AMR)

AF:

0.0875

AC:

1337

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3466

East Asian (EAS)

AF:

0.582

AC:

2999

AN:

5154

South Asian (SAS)

AF:

0.0973

AC:

469

AN:

4820

European-Finnish (FIN)

AF:

0.0174

AC:

184

AN:

10584

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0185

AC:

1261

AN:

67994

Other (OTH)

AF:

0.0880

AC:

186

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

600

1200

1799

2399

2999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0616

Hom.:

105

Bravo

AF:

0.120

Asia WGS

AF:

0.253

AC:

881

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.77

(source)

DANN

Benign

0.23

PhyloP100

-0.38

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