Genetic Variant NRG1:p.Ala104_Ala105del (chr8-31640283-AGGCGGC-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000520407.5(NRG1):c.311_316delCGGCGG(p.Ala104_Ala105del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000925 in 972,688 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A104A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000093 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NRG1
ENST00000520407.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.54

Publications

0 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:

ENSG00000302325 (HGNC:):

ENSG00000302325 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NRG1	NM_013962.3 link	c.311_316delCGGCGG	p.Ala104_Ala105del	disruptive_inframe_deletion	Exon 1 of 5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 link	c.311_316delCGGCGG	p.Ala104_Ala105del	disruptive_inframe_deletion	Exon 1 of 13	XP_011542814.2
NRG1	XM_017013367.2 link	c.311_316delCGGCGG	p.Ala104_Ala105del	disruptive_inframe_deletion	Exon 1 of 11	XP_016868856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
NRG1	ENST00000520407.5 link	c.311_316delCGGCGG	p.Ala104_Ala105del	disruptive_inframe_deletion	Exon 1 of 5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000650866.1 link	c.37+864_37+869delCGGCGG		intron_variant	Intron 1 of 12		ENSP00000499045.1	A0A494C1F5
NRG1	ENST00000652698.1 link	c.37+864_37+869delCGGCGG		intron_variant	Intron 1 of 11		ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

147342

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000925

AC:

AN:

972688

Hom.:

AF XY:

0.0000131

AC XY:

AN XY:

458254

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

18894

American (AMR)

AF:

0.00

AC:

AN:

4992

Ashkenazi Jewish (ASJ)

AF:

0.000108

AC:

AN:

9266

East Asian (EAS)

AF:

0.00

AC:

AN:

16590

South Asian (SAS)

AF:

0.00

AC:

AN:

18552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2354

European-Non Finnish (NFE)

AF:

0.00000705

AC:

AN:

851086

Other (OTH)

AF:

0.0000563

AC:

AN:

35554

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

147342

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71716

African (AFR)

AF:

0.00

AC:

AN:

40876

American (AMR)

AF:

0.00

AC:

AN:

14848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.00

AC:

AN:

5020

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66164

Other (OTH)

AF:

0.00

AC:

AN:

2036

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.5

Mutation Taster

=157/43

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

8-31640283-AGGCGGCGGC-AGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over