Genetic Variant NRG1:c.804-26dupA (chr8-32756368-C-CA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_013964.5(NRG1):c.804-26dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,570,644 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

NRG1
NM_013964.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.05

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

new If you want to explore the variant's impact on the transcript NM_013964.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013964.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NRG1	NM_013964.5	MANE Select	c.804-26dupA	intron	N/A	NP_039258.1	Q02297-1
NRG1	NM_001322205.2		c.984-26dupA	intron	N/A	NP_001309134.1	A0A494C0Q4
NRG1	NM_013956.5		c.819-26dupA	intron	N/A	NP_039250.2	Q02297-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NRG1	ENST00000405005.8	TSL:1 MANE Select	c.804-35_804-34insA	intron	N/A	ENSP00000384620.2	Q02297-1
NRG1	ENST00000287842.7	TSL:1	c.819-35_819-34insA	intron	N/A	ENSP00000287842.4	Q02297-6
NRG1	ENST00000356819.7	TSL:1	c.795-35_795-34insA	intron	N/A	ENSP00000349275.6	Q02297-7

Frequencies

GnomAD3 genomes

AF:

0.000186

AC:

AN:

150386

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000265

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.000421

Gnomad FIN

AF:

0.000196

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000485

GnomAD2 exomes

AF:

0.000710

AC:

142

AN:

199974

AF XY:

0.000779

show subpopulations

Gnomad AFR exome

AF:

0.000674

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000289

Gnomad EAS exome

AF:

0.00116

Gnomad FIN exome

AF:

0.00124

Gnomad NFE exome

AF:

0.000383

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000299

AC:

424

AN:

1420148

Hom.:

Cov.:

AF XY:

0.000319

AC XY:

225

AN XY:

706184

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000346

AC:

AN:

31774

American (AMR)

AF:

0.000842

AC:

AN:

40374

Ashkenazi Jewish (ASJ)

AF:

0.000162

AC:

AN:

24650

East Asian (EAS)

AF:

0.00145

AC:

AN:

38554

South Asian (SAS)

AF:

0.000427

AC:

AN:

81942

European-Finnish (FIN)

AF:

0.000584

AC:

AN:

51372

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5530

European-Non Finnish (NFE)

AF:

0.000211

AC:

229

AN:

1087592

Other (OTH)

AF:

0.000411

AC:

AN:

58360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000213

AC:

AN:

150496

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

AN XY:

73404

show subpopulations

African (AFR)

AF:

0.000316

AC:

AN:

41102

American (AMR)

AF:

0.000265

AC:

AN:

15120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.000390

AC:

AN:

5122

South Asian (SAS)

AF:

0.000422

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.000196

AC:

AN:

10180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000119

AC:

AN:

67506

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00181

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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8-32756368-CAA-CAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over