8-32544043-T-C

Variant names:

• chr8-32544043-T-C
• rs6468119
• ENST00000520407.5:c.746-51785T>C

Variant summary

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

The ENST00000520407.5(NRG1):​c.746-51785T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 152,020 control chromosomes in the GnomAD database, including 24,637 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 0.56 (24637 hom., cov: 32)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• Publications: 8 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=-0.67).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.79 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.38-51785T>C		intron	N/A	NP_001153471.1
	NRG1	NM_001159995.3		c.38-51785T>C		intron	N/A	NP_001153467.1
	NRG1	NM_001160001.3		c.38-51785T>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.746-51785T>C		intron	N/A	ENSP00000434640.1
	NRG1	ENST00000523534.5	TSL:5	c.305-51785T>C		intron	N/A	ENSP00000429067.1
	NRG1	ENST00000650866.1		c.38-51785T>C		intron	N/A	ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85722 AN: 151902 Hom.: 24616 Cov.: 32

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.810

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.557

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

GnomAD4 genome AF: 0.564 AC: 85780 AN: 152020 Hom.: 24637 Cov.: 32 AF XY: 0.569 AC XY: 42274 AN XY: 74306

African (AFR) AF: 0.470 AC: 19495 AN: 41454

American (AMR) AF: 0.651 AC: 9928 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1687 AN: 3464

East Asian (EAS) AF: 0.811 AC: 4188 AN: 5164

South Asian (SAS) AF: 0.561 AC: 2703 AN: 4820

European-Finnish (FIN) AF: 0.647 AC: 6843 AN: 10570

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.576 AC: 39178 AN: 67974

Other (OTH) AF: 0.555 AC: 1170 AN: 2110

Alfa AF: 0.574 Hom.: 61958

Bravo AF: 0.564

Asia WGS AF: 0.660 AC: 2294 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.9
DANN	Benign	0.92
PhyloP100		0.087
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: rs6468119; hg19: chr8-32401561;