rs1481765

Variant names:

• chr8-32221455-G-A
• rs1481765
• ENST00000520407.5:c.746-374373G>A

Variant summary

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

The ENST00000520407.5(NRG1):​c.746-374373G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,042 control chromosomes in the GnomAD database, including 8,507 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 0.24 (8507 hom., cov: 33)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.331
• Publications: 2 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

ENSG00000305898 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.38-374373G>A		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.38-374373G>A		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.38-374373G>A		intron_variant	Intron 1 of 10		NP_001153473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000520407.5	c.746-374373G>A		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
ENSG00000305898	ENST00000813852.1	n.8C>T		non_coding_transcript_exon_variant	Exon 1 of 2
NRG1	ENST00000523534.5	c.305-374373G>A		intron_variant	Intron 1 of 12	5		ENSP00000429067.1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36316 AN: 151926 Hom.: 8495 Cov.: 33

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.0962

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.239 AC: 36377 AN: 152042 Hom.: 8507 Cov.: 33 AF XY: 0.231 AC XY: 17206 AN XY: 74352

African (AFR) AF: 0.613 AC: 25366 AN: 41400

American (AMR) AF: 0.157 AC: 2399 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 496 AN: 3464

East Asian (EAS) AF: 0.00445 AC: 23 AN: 5170

South Asian (SAS) AF: 0.131 AC: 631 AN: 4812

European-Finnish (FIN) AF: 0.0309 AC: 327 AN: 10592

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.0962 AC: 6544 AN: 68006

Other (OTH) AF: 0.231 AC: 487 AN: 2110

Alfa AF: 0.134 Hom.: 1529

Bravo AF: 0.263

Asia WGS AF: 0.104 AC: 361 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.0
DANN	Benign	0.71
PhyloP100		0.33
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: rs1481765; hg19: chr8-32078971;