NM_013964.5:c.503-54176G>A

Variant names:

• chr8-32673773-G-A
• rs764059
• NM_013964.5:c.503-54176G>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.503-54176G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 152,134 control chromosomes in the GnomAD database, including 50,959 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 0.81 (50959 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.589
• Publications: 4 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 (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.503-54176G>A		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.503-54176G>A		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122649 AN: 152016 Hom.: 50929 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.946

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.889

Gnomad OTH AF: 0.804

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

GnomAD4 genome AF: 0.807 AC: 122736 AN: 152134 Hom.: 50959 Cov.: 32 AF XY: 0.813 AC XY: 60444 AN XY: 74392

African (AFR) AF: 0.588 AC: 24378 AN: 41440

American (AMR) AF: 0.856 AC: 13086 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2796 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5176 AN: 5182

South Asian (SAS) AF: 0.861 AC: 4159 AN: 4828

European-Finnish (FIN) AF: 0.946 AC: 10033 AN: 10604

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.889 AC: 60439 AN: 68010

Other (OTH) AF: 0.804 AC: 1698 AN: 2112

Alfa AF: 0.867 Hom.: 29132

Bravo AF: 0.791

Asia WGS AF: 0.901 AC: 3131 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	4.7
DANN	Benign	0.74
PhyloP100		0.59
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: rs764059; hg19: chr8-32531292;