Genetic Variant NM_013964.5:c.700+1211A>G (chr8-32743286-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_013964.5(NRG1):c.700+1211A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 918,786 control chromosomes in the GnomAD database, including 365 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 0.023 ( 68 hom., cov: 32)

Exomes 𝑓: 0.026 ( 297 hom. )

Consequence

NRG1
NM_013964.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.17

Publications

1 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=-0.86).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0229 (3492/152206) while in subpopulation NFE AF = 0.0299 (2032/67996). AF 95% confidence interval is 0.0288. There are 68 homozygotes in GnomAd4. There are 1817 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 68 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5 link	c.700+1211A>G		intron_variant	Intron 7 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.700+1211A>G		intron_variant	Intron 7 of 11	1	NM_013964.5	ENSP00000384620.2		Q02297-1

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3492

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00473

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0205

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0740

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0299

Gnomad OTH

AF:

0.0229

GnomAD4 exome

AF:

0.0259

AC:

19841

AN:

766580

Hom.:

297

Cov.:

AF XY:

0.0258

AC XY:

9161

AN XY:

355540

show subpopulations

African (AFR)

AF:

0.00299

AC:

AN:

14398

American (AMR)

AF:

0.0136

AC:

AN:

880

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

124

AN:

4738

East Asian (EAS)

AF:

0.000307

AC:

AN:

3258

South Asian (SAS)

AF:

0.00883

AC:

133

AN:

15064

European-Finnish (FIN)

AF:

0.0504

AC:

AN:

258

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

1482

European-Non Finnish (NFE)

AF:

0.0270

AC:

18935

AN:

701534

Other (OTH)

AF:

0.0224

AC:

560

AN:

24968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

877

1753

2630

3506

4383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

986

1972

2958

3944

4930

<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:

0.0229

AC:

3492

AN:

152206

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

1817

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00471

AC:

196

AN:

41570

American (AMR)

AF:

0.0206

AC:

314

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00684

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0740

AC:

783

AN:

10586

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0299

AC:

2032

AN:

67996

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

171

341

512

682

853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0261

Hom.:

Bravo

AF:

0.0179

Asia WGS

AF:

0.00231

AC:

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

7.0

(source)

DANN

Benign

0.50

PhyloP100

3.2

Mutation Taster

=100/0

polymorphism

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over