8-32548461-T-C

Variant names:

• chr8-32548461-T-C
• rs7820838
• NM_013964.5:c.-266T>C

Variant summary

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

The NM_013964.5(NRG1):​c.-266T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.779 in 1,170,154 control chromosomes in the GnomAD database, including 356,018 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 (46930 hom., cov: 32)
  • Exomes 𝑓: 0.78 (309088 hom.)
• Consequence: NRG1 NM_013964.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.369
• Publications: 16 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.-266T>C		5_prime_UTR_variant	Exon 1 of 12	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.-266T>C		5_prime_UTR_variant	Exon 1 of 12	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119071 AN: 151714 Hom.: 46892 Cov.: 32

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.866

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.798

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.794

GnomAD4 exome AF: 0.779 AC: 792843 AN: 1018332 Hom.: 309088 Cov.: 70 AF XY: 0.778 AC XY: 372559 AN XY: 478786

African (AFR) AF: 0.754 AC: 15432 AN: 20464

American (AMR) AF: 0.864 AC: 4865 AN: 5630

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 8632 AN: 11358

East Asian (EAS) AF: 0.866 AC: 16657 AN: 19242

South Asian (SAS) AF: 0.657 AC: 13760 AN: 20930

European-Finnish (FIN) AF: 0.807 AC: 13640 AN: 16912

Middle Eastern (MID) AF: 0.729 AC: 1870 AN: 2566

European-Non Finnish (NFE) AF: 0.780 AC: 687826 AN: 881986

Other (OTH) AF: 0.769 AC: 30161 AN: 39244

GnomAD4 genome AF: 0.785 AC: 119159 AN: 151822 Hom.: 46930 Cov.: 32 AF XY: 0.785 AC XY: 58252 AN XY: 74182

African (AFR) AF: 0.762 AC: 31593 AN: 41462

American (AMR) AF: 0.866 AC: 13242 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2664 AN: 3466

East Asian (EAS) AF: 0.799 AC: 3980 AN: 4984

South Asian (SAS) AF: 0.658 AC: 3174 AN: 4826

European-Finnish (FIN) AF: 0.824 AC: 8721 AN: 10586

Middle Eastern (MID) AF: 0.724 AC: 210 AN: 290

European-Non Finnish (NFE) AF: 0.783 AC: 53141 AN: 67892

Other (OTH) AF: 0.790 AC: 1668 AN: 2112

Alfa AF: 0.729 Hom.: 2219

Bravo AF: 0.791

Asia WGS AF: 0.710 AC: 2448 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.77
PhyloP100		-0.37
PromoterAI		0.030	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7820838; hg19: chr8-32405979;