8-32760195-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013964.5(NRG1):c.1062-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 1,613,620 control chromosomes in the GnomAD database, including 944 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 60 hom., cov: 32)

Exomes 𝑓: 0.033 ( 884 hom. )

Consequence

NRG1
NM_013964.5 splice_region, intron

Scores

Splicing: ADA: 0.00001712

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.232

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104382608

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 8-32760195-C-T is Benign according to our data. Variant chr8-32760195-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1285117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0215 (3273/152208) while in subpopulation NFE AF = 0.0349 (2372/68020). AF 95% confidence interval is 0.0337. There are 60 homozygotes in GnomAd4. There are 1437 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5 link	c.1062-5C>T		splice_region_variant, intron_variant	Intron 10 of 11	ENST00000405005.8	NP_039258.1	Q02297-1Q6PK61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8 link	c.1062-5C>T		splice_region_variant, intron_variant	Intron 10 of 11	1	NM_013964.5	ENSP00000384620.2		Q02297-1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3276

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00712

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0216

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.00812

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0349

Gnomad OTH

AF:

0.0283

GnomAD2 exomes

AF:

0.0226

AC:

5669

AN:

250366

AF XY:

0.0238

show subpopulations

Gnomad AFR exome

AF:

0.00550

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.00718

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00795

Gnomad NFE exome

AF:

0.0368

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0328

AC:

47897

AN:

1461412

Hom.:

884

Cov.:

AF XY:

0.0323

AC XY:

23493

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.00514

AC:

172

AN:

33472

American (AMR)

AF:

0.0171

AC:

765

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00746

AC:

195

AN:

26122

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39666

South Asian (SAS)

AF:

0.0175

AC:

1505

AN:

86222

European-Finnish (FIN)

AF:

0.00962

AC:

513

AN:

53330

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0386

AC:

42902

AN:

1111738

Other (OTH)

AF:

0.0291

AC:

1756

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2151

4302

6453

8604

10755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1576

3152

4728

6304

7880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0215

AC:

3273

AN:

152208

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

1437

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00710

AC:

295

AN:

41536

American (AMR)

AF:

0.0215

AC:

329

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.0164

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00812

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0349

AC:

2372

AN:

68020

Other (OTH)

AF:

0.0275

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

163

325

488

650

813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0298

Hom.:

131

Bravo

AF:

0.0224

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0380

EpiControl

AF:

0.0383

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Schizophrenia 6

Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

European Non-Finnish population allele frequency is 3.371% (rs79223941, 3,276/152,090 alleles, 48 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.3.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

NRG1-related disorder

Benign:1

Oct 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.5

(source)

DANN

Benign

0.40

PhyloP100

0.23

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over