NM_013964.5:c.503-21543A>G

Variant names:

• chr8-32706406-A-G
• rs2919381
• NM_013964.5:c.503-21543A>G

Variant summary

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

The NM_013964.5(NRG1):​c.503-21543A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 152,054 control chromosomes in the GnomAD database, including 15,129 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 0.42 (15129 hom., cov: 33)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.671
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.503-21543A>G		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.503-21543A>G		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63371 AN: 151936 Hom.: 15112 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.444

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

GnomAD4 genome AF: 0.417 AC: 63411 AN: 152054 Hom.: 15129 Cov.: 33 AF XY: 0.416 AC XY: 30954 AN XY: 74324

African (AFR) AF: 0.173 AC: 7175 AN: 41516

American (AMR) AF: 0.439 AC: 6705 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1533 AN: 3472

East Asian (EAS) AF: 0.544 AC: 2805 AN: 5160

South Asian (SAS) AF: 0.617 AC: 2972 AN: 4816

European-Finnish (FIN) AF: 0.447 AC: 4716 AN: 10560

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.531 AC: 36071 AN: 67928

Other (OTH) AF: 0.451 AC: 953 AN: 2112

Alfa AF: 0.508 Hom.: 30803

Bravo AF: 0.400

Asia WGS AF: 0.573 AC: 1988 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.8
DANN	Benign	0.66
PhyloP100		0.67
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: rs2919381; hg19: chr8-32563924;