8-31640283-AGGC-A

Variant names:

• chr8-31640283-AGGC-A
• rs770519581
• ENST00000520407.5:c.314_316delCGG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_013962.3(NRG1):​c.314_316delCGG​(p.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 0.000936 in 1,108,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: NRG1 NM_013962.3 disruptive_inframe_deletion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.86
• Publications: 0 publications found

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

ENSG00000302325 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 8-31640283-AGGC-A is Benign according to our data. Variant chr8-31640283-AGGC-A is described in ClinVar as [Likely_benign]. Clinvar id is 3038071.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013962.3	c.314_316delCGG	p.Ala105del	disruptive_inframe_deletion	Exon 1 of 5		NP_039256.2
NRG1	XM_011544512.3	c.314_316delCGG	p.Ala105del	disruptive_inframe_deletion	Exon 1 of 13		XP_011542814.2
NRG1	XM_017013367.2	c.314_316delCGG	p.Ala105del	disruptive_inframe_deletion	Exon 1 of 11		XP_016868856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000520407.5	c.314_316delCGG	p.Ala105del	disruptive_inframe_deletion	Exon 1 of 5	1		ENSP00000434640.1
NRG1	ENST00000650866.1	c.37+867_37+869delCGG		intron_variant	Intron 1 of 12			ENSP00000499045.1
NRG1	ENST00000652698.1	c.37+867_37+869delCGG		intron_variant	Intron 1 of 11			ENSP00000499008.1

Frequencies

GnomAD3 genomes AF: 0.0000407 AC: 6 AN: 147334 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000489

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: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000453

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 312 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00107 AC: 1032 AN: 961094 Hom.: 0 AF XY: 0.00114 AC XY: 518 AN XY: 452742

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

African (AFR) AF: 0.00134 AC: 25 AN: 18652

American (AMR) AF: 0.00538 AC: 26 AN: 4834

Ashkenazi Jewish (ASJ) AF: 0.00386 AC: 35 AN: 9074

East Asian (EAS) AF: 0.00631 AC: 102 AN: 16154

South Asian (SAS) AF: 0.000436 AC: 8 AN: 18354

European-Finnish (FIN) AF: 0.00753 AC: 112 AN: 14878

Middle Eastern (MID) AF: 0.00215 AC: 5 AN: 2324

European-Non Finnish (NFE) AF: 0.000785 AC: 661 AN: 841780

Other (OTH) AF: 0.00166 AC: 58 AN: 35044

⚠️ 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.

GnomAD4 genome AF: 0.0000407 AC: 6 AN: 147334 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71714

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

African (AFR) AF: 0.0000489 AC: 2 AN: 40876

American (AMR) AF: 0.00 AC: 0 AN: 14848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5020

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.000111 AC: 1 AN: 8988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000453 AC: 3 AN: 66160

Other (OTH) AF: 0.00 AC: 0 AN: 2036

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NRG1-related disorder Benign:1

Jul 17, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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
PhyloP100		1.9
Mutation Taster		=72/28	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs770519581; hg19: chr8-31497799; COSMIC: COSV109445650;