ENST00000520407.5:c.746-197483T>C

Variant names:

• chr8-32398345-T-C
• rs12114401
• ENST00000520407.5:c.746-197483T>C

Variant summary

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

The ENST00000520407.5(NRG1):​c.746-197483T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 151,608 control chromosomes in the GnomAD database, including 10,277 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 0.36 (10277 hom., cov: 30)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.437
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000520407.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_001159999.3		c.38-197483T>C		intron	N/A	NP_001153471.1
	NRG1	NM_001159995.3		c.38-197483T>C		intron	N/A	NP_001153467.1
	NRG1	NM_001160001.3		c.38-197483T>C		intron	N/A	NP_001153473.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000520407.5	TSL:1	c.746-197483T>C		intron	N/A	ENSP00000434640.1
	NRG1	ENST00000523534.5	TSL:5	c.305-197483T>C		intron	N/A	ENSP00000429067.1
	NRG1	ENST00000650866.1		c.38-197483T>C		intron	N/A	ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54287 AN: 151490 Hom.: 10263 Cov.: 30

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.553

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.403

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

GnomAD4 genome AF: 0.358 AC: 54332 AN: 151608 Hom.: 10277 Cov.: 30 AF XY: 0.352 AC XY: 26105 AN XY: 74068

African (AFR) AF: 0.405 AC: 16712 AN: 41250

American (AMR) AF: 0.317 AC: 4831 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1745 AN: 3470

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5176

South Asian (SAS) AF: 0.257 AC: 1237 AN: 4806

European-Finnish (FIN) AF: 0.286 AC: 2999 AN: 10474

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.373 AC: 25313 AN: 67886

Other (OTH) AF: 0.398 AC: 839 AN: 2108

Alfa AF: 0.368 Hom.: 1867

Bravo AF: 0.363

Asia WGS AF: 0.157 AC: 550 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.4
DANN	Benign	0.58
PhyloP100		-0.44
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: rs12114401; hg19: chr8-32255861;