8-31640283-AGGC-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The ENST00000520407.5(NRG1):c.314_316del(p.Ala105del) variant causes a 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: NRG1 ENST00000520407.5 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.86

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 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 criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013962.3	c.314_316del	p.Ala105del	inframe_deletion	1/5
NRG1	XM_011544512.3	c.314_316del	p.Ala105del	inframe_deletion	1/13
NRG1	XM_017013367.2	c.314_316del	p.Ala105del	inframe_deletion	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000520407.5	c.314_316del	p.Ala105del	inframe_deletion	1/5	1
NRG1	ENST00000519301.6	c.37+867_37+869del		intron_variant		5
NRG1	ENST00000650866.1	c.37+867_37+869del		intron_variant

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

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

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00538

Gnomad4 ASJ exome AF: 0.00386

Gnomad4 EAS exome AF: 0.00631

Gnomad4 SAS exome AF: 0.000436

Gnomad4 FIN exome AF: 0.00753

Gnomad4 NFE exome AF: 0.000785

Gnomad4 OTH exome AF: 0.00166

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

Gnomad4 AFR AF: 0.0000489

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000111

Gnomad4 NFE AF: 0.0000453

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NRG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2020

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs770519581; hg19: chr8-31497799;