8-31673944-G-C

Variant names:

• chr8-31673944-G-C
• rs10098401
• ENST00000520407.5:c.745+33215G>C

Variant summary

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

The ENST00000520407.5(NRG1):​c.745+33215G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 151,944 control chromosomes in the GnomAD database, including 4,339 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 0.22 (4339 hom., cov: 32)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.124
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 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.37+34513G>C		intron	N/A	NP_001153471.1
	NRG1	NM_001159995.3		c.37+34513G>C		intron	N/A	NP_001153467.1
	NRG1	NM_001160001.3		c.37+34513G>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.745+33215G>C		intron	N/A	ENSP00000434640.1
	NRG1	ENST00000523534.5	TSL:5	c.304+33215G>C		intron	N/A	ENSP00000429067.1
	NRG1	ENST00000650866.1		c.37+34513G>C		intron	N/A	ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32940 AN: 151830 Hom.: 4338 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.217 AC: 32962 AN: 151944 Hom.: 4339 Cov.: 32 AF XY: 0.219 AC XY: 16299 AN XY: 74258

African (AFR) AF: 0.115 AC: 4751 AN: 41490

American (AMR) AF: 0.220 AC: 3359 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 963 AN: 3466

East Asian (EAS) AF: 0.594 AC: 3073 AN: 5172

South Asian (SAS) AF: 0.315 AC: 1518 AN: 4814

European-Finnish (FIN) AF: 0.193 AC: 2032 AN: 10516

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16464 AN: 67940

Other (OTH) AF: 0.206 AC: 434 AN: 2102

Alfa AF: 0.215 Hom.: 483

Bravo AF: 0.214

Asia WGS AF: 0.377 AC: 1306 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.9
DANN	Benign	0.47
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: rs10098401; hg19: chr8-31531460;