Genetic Variant ENST00000520407.5:c.745+1163C>T (chr8-31641892-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 ENST00000520407.5(NRG1):c.745+1163C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 151,828 control chromosomes in the GnomAD database, including 4,737 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 0.24 ( 4737 hom., cov: 32)

Exomes 𝑓: 0.17 ( 0 hom. )

Consequence

NRG1
ENST00000520407.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.43

Publications

7 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=-0.55).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
NRG1	NM_001159999.3 link	c.37+2461C>T	intron_variant	Intron 1 of 12	NP_001153471.1	Q02297E3SFM9A6MW55A0A494C1F5
NRG1	NM_001159995.3 link	c.37+2461C>T	intron_variant	Intron 1 of 11	NP_001153467.1	Q02297E3SFM9A6MW56A0A494C1F8
NRG1	NM_001160001.3 link	c.37+2461C>T	intron_variant	Intron 1 of 10	NP_001153473.1	Q02297-11E3SFM9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
NRG1	ENST00000520407.5 link	c.745+1163C>T	intron_variant	Intron 1 of 4	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5 link	c.304+1163C>T	intron_variant	Intron 1 of 12	5	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1 link	c.37+2461C>T	intron_variant	Intron 1 of 12		ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.238

AC:

36125

AN:

151704

Hom.:

4736

Cov.:

show subpopulations

Gnomad AFR

AF:

0.304

Gnomad AMI

AF:

0.0954

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.302

Gnomad EAS

AF:

0.0124

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.235

Gnomad OTH

AF:

0.283

GnomAD4 exome

AF:

0.167

AC:

AN:

Hom.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.238

AC:

36145

AN:

151822

Hom.:

4737

Cov.:

AF XY:

0.230

AC XY:

17069

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.304

AC:

12586

AN:

41380

American (AMR)

AF:

0.223

AC:

3400

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

1045

AN:

3462

East Asian (EAS)

AF:

0.0124

AC:

AN:

5156

South Asian (SAS)

AF:

0.121

AC:

578

AN:

4776

European-Finnish (FIN)

AF:

0.164

AC:

1730

AN:

10522

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.235

AC:

15989

AN:

67958

Other (OTH)

AF:

0.280

AC:

591

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1366

2733

4099

5466

6832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<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:

0.236

Hom.:

5152

Bravo

AF:

0.249

Asia WGS

AF:

0.0840

AC:

290

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

1.4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over