rs12542743

Variant names:

• chr8-32460839-T-C
• rs12542743
• ENST00000520407.5:c.746-134989T>C

Variant summary

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

The ENST00000520407.5(NRG1):​c.746-134989T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 151,896 control chromosomes in the GnomAD database, including 20,311 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 0.51 (20311 hom., cov: 32)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• Publications: 12 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.38-134989T>C		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.38-134989T>C		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.38-134989T>C		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.746-134989T>C		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.305-134989T>C		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.38-134989T>C		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77806 AN: 151776 Hom.: 20288 Cov.: 32

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.510

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

GnomAD4 genome AF: 0.513 AC: 77879 AN: 151896 Hom.: 20311 Cov.: 32 AF XY: 0.514 AC XY: 38143 AN XY: 74222

African (AFR) AF: 0.493 AC: 20430 AN: 41434

American (AMR) AF: 0.576 AC: 8786 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1532 AN: 3470

East Asian (EAS) AF: 0.264 AC: 1361 AN: 5158

South Asian (SAS) AF: 0.490 AC: 2359 AN: 4818

European-Finnish (FIN) AF: 0.571 AC: 6000 AN: 10510

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.528 AC: 35849 AN: 67944

Other (OTH) AF: 0.509 AC: 1074 AN: 2110

Alfa AF: 0.514 Hom.: 7919

Bravo AF: 0.512

Asia WGS AF: 0.441 AC: 1533 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.21
DANN	Benign	0.36
PhyloP100		-1.3
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: rs12542743; hg19: chr8-32318355; COSMIC: COSV73060619;