8-32685523-A-T

Variant names:

• chr8-32685523-A-T
• rs7823899
• NM_013964.5:c.503-42426A>T

Variant summary

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

The NM_013964.5(NRG1):​c.503-42426A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 151,980 control chromosomes in the GnomAD database, including 19,544 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 0.51 (19544 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.470
• Publications: 2 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.503-42426A>T		intron_variant	Intron 5 of 11	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.503-42426A>T		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76881 AN: 151860 Hom.: 19529 Cov.: 32

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.514

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.506 AC: 76927 AN: 151980 Hom.: 19544 Cov.: 32 AF XY: 0.508 AC XY: 37729 AN XY: 74272

African (AFR) AF: 0.502 AC: 20805 AN: 41416

American (AMR) AF: 0.482 AC: 7355 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1797 AN: 3472

East Asian (EAS) AF: 0.486 AC: 2510 AN: 5166

South Asian (SAS) AF: 0.470 AC: 2262 AN: 4814

European-Finnish (FIN) AF: 0.576 AC: 6073 AN: 10548

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34436 AN: 67980

Other (OTH) AF: 0.509 AC: 1076 AN: 2112

Alfa AF: 0.495 Hom.: 2215

Bravo AF: 0.504

Asia WGS AF: 0.484 AC: 1682 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.43
PhyloP100		0.47
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: rs7823899; hg19: chr8-32543041;