ENST00000520407.5:c.746-48450C>T

Variant names:

• chr8-32547378-C-T
• rs3802158
• ENST00000520407.5:c.746-48450C>T

Variant summary

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

The ENST00000520407.5(NRG1):​c.746-48450C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 151,902 control chromosomes in the GnomAD database, including 12,716 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 0.39 (12716 hom., cov: 31)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.116
• Publications: 5 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.38-48450C>T		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.38-48450C>T		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.38-48450C>T		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.746-48450C>T		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.305-48450C>T		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.38-48450C>T		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59438 AN: 151784 Hom.: 12709 Cov.: 31

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.387

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

GnomAD4 genome AF: 0.391 AC: 59469 AN: 151902 Hom.: 12716 Cov.: 31 AF XY: 0.394 AC XY: 29275 AN XY: 74212

African (AFR) AF: 0.228 AC: 9439 AN: 41392

American (AMR) AF: 0.486 AC: 7418 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1338 AN: 3466

East Asian (EAS) AF: 0.178 AC: 916 AN: 5152

South Asian (SAS) AF: 0.408 AC: 1966 AN: 4820

European-Finnish (FIN) AF: 0.558 AC: 5883 AN: 10548

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31172 AN: 67952

Other (OTH) AF: 0.388 AC: 818 AN: 2108

Alfa AF: 0.440 Hom.: 5329

Bravo AF: 0.378

Asia WGS AF: 0.346 AC: 1204 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.83
PhyloP100		0.12
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: rs3802158; hg19: chr8-32404896;