8-32554841-A-G

Variant names:

• chr8-32554841-A-G
• rs2439312
• NM_013964.5:c.100+6015A>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.100+6015A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.785 in 151,834 control chromosomes in the GnomAD database, including 46,935 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 0.78 (46935 hom., cov: 30)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.467
• Publications: 23 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.100+6015A>G		intron_variant	Intron 1 of 11	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.100+6015A>G		intron_variant	Intron 1 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119063 AN: 151714 Hom.: 46892 Cov.: 30

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.823

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.794

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

GnomAD4 genome AF: 0.785 AC: 119162 AN: 151834 Hom.: 46935 Cov.: 30 AF XY: 0.785 AC XY: 58249 AN XY: 74170

African (AFR) AF: 0.763 AC: 31557 AN: 41386

American (AMR) AF: 0.865 AC: 13209 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2663 AN: 3470

East Asian (EAS) AF: 0.800 AC: 4122 AN: 5150

South Asian (SAS) AF: 0.658 AC: 3165 AN: 4810

European-Finnish (FIN) AF: 0.823 AC: 8624 AN: 10476

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53189 AN: 67974

Other (OTH) AF: 0.790 AC: 1655 AN: 2096

Alfa AF: 0.786 Hom.: 222492

Bravo AF: 0.791

Asia WGS AF: 0.710 AC: 2472 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.0
DANN	Benign	0.69
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: rs2439312; hg19: chr8-32412359;