rs4531002

Variant names:

• chr8-32644468-C-T
• rs4531002
• NM_013964.5:c.502+27583C>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.502+27583C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 152,008 control chromosomes in the GnomAD database, including 8,057 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 0.31 (8057 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• Publications: 11 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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.502+27583C>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.502+27583C>T		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47410 AN: 151890 Hom.: 8053 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.313

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

GnomAD4 genome AF: 0.312 AC: 47430 AN: 152008 Hom.: 8057 Cov.: 32 AF XY: 0.312 AC XY: 23202 AN XY: 74310

African (AFR) AF: 0.198 AC: 8220 AN: 41468

American (AMR) AF: 0.351 AC: 5356 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1083 AN: 3464

East Asian (EAS) AF: 0.125 AC: 647 AN: 5168

South Asian (SAS) AF: 0.250 AC: 1206 AN: 4820

European-Finnish (FIN) AF: 0.429 AC: 4522 AN: 10550

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.373 AC: 25320 AN: 67954

Other (OTH) AF: 0.313 AC: 662 AN: 2114

Alfa AF: 0.347 Hom.: 18007

Bravo AF: 0.300

Asia WGS AF: 0.210 AC: 729 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.1
DANN	Benign	0.70
PhyloP100		0.061
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: rs4531002; hg19: chr8-32501987;