chr8-32646882-G-A

Variant names:

• chr8-32646882-G-A
• rs7825588
• NM_013964.5:c.502+29997G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013964.5(NRG1):​c.502+29997G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 984,474 control chromosomes in the GnomAD database, including 6,286 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 0.11 (1040 hom., cov: 30)
  • Exomes 𝑓: 0.11 (5246 hom.)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78
• Publications: 12 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_013964.5	MANE Select	c.502+29997G>A		intron	N/A	NP_039258.1
	NRG1	NM_013956.5		c.502+29997G>A		intron	N/A	NP_039250.2
	NRG1	NM_013957.5		c.502+29997G>A		intron	N/A	NP_039251.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.502+29997G>A		intron	N/A	ENSP00000384620.2
	NRG1	ENST00000287842.7	TSL:1	c.502+29997G>A		intron	N/A	ENSP00000287842.4
	NRG1	ENST00000356819.7	TSL:1	c.502+29997G>A		intron	N/A	ENSP00000349275.6

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16860 AN: 151264 Hom.: 1039 Cov.: 30

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0867

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.0975

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.110

GnomAD4 exome AF: 0.112 AC: 92983 AN: 833092 Hom.: 5246 Cov.: 29 AF XY: 0.112 AC XY: 43060 AN XY: 384702

African (AFR) AF: 0.152 AC: 2406 AN: 15786

American (AMR) AF: 0.0661 AC: 65 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 894 AN: 5152

East Asian (EAS) AF: 0.000826 AC: 3 AN: 3630

South Asian (SAS) AF: 0.0739 AC: 1216 AN: 16460

European-Finnish (FIN) AF: 0.105 AC: 29 AN: 276

Middle Eastern (MID) AF: 0.155 AC: 251 AN: 1620

European-Non Finnish (NFE) AF: 0.112 AC: 85160 AN: 761886

Other (OTH) AF: 0.108 AC: 2959 AN: 27298

GnomAD4 genome AF: 0.111 AC: 16869 AN: 151382 Hom.: 1040 Cov.: 30 AF XY: 0.108 AC XY: 8020 AN XY: 73926

African (AFR) AF: 0.142 AC: 5842 AN: 41126

American (AMR) AF: 0.0866 AC: 1318 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 578 AN: 3468

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5154

South Asian (SAS) AF: 0.0628 AC: 300 AN: 4774

European-Finnish (FIN) AF: 0.0975 AC: 1023 AN: 10496

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7461 AN: 67834

Other (OTH) AF: 0.108 AC: 227 AN: 2100

Alfa AF: 0.115 Hom.: 1848

Bravo AF: 0.115

Asia WGS AF: 0.0460 AC: 162 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.5
DANN	Benign	0.57
PhyloP100		2.8
PromoterAI		0.039	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs7825588; hg19: chr8-32504401;