chr8-32747325-G-A

Variant names:

• chr8-32747325-G-A
• rs3757933
• NM_013964.5:c.700+5250G>A

Variant summary

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

The NM_001322205.2(NRG1):​c.857-2236G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 151,824 control chromosomes in the GnomAD database, including 4,838 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 0.23 (4838 hom., cov: 30)
• Consequence: NRG1 NM_001322205.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.151
• Publications: 1 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322205.2. 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_013964.5	MANE Select	c.700+5250G>A		intron	N/A	NP_039258.1
	NRG1	NM_001322205.2		c.857-2236G>A		intron	N/A	NP_001309134.1
	NRG1	NM_013956.5		c.692-2236G>A		intron	N/A	NP_039250.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.700+5250G>A		intron	N/A	ENSP00000384620.2
	NRG1	ENST00000287842.7	TSL:1	c.692-2236G>A		intron	N/A	ENSP00000287842.4
	NRG1	ENST00000356819.7	TSL:1	c.691+4592G>A		intron	N/A	ENSP00000349275.6

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35497 AN: 151706 Hom.: 4828 Cov.: 30

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.229

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

GnomAD4 genome AF: 0.234 AC: 35529 AN: 151824 Hom.: 4838 Cov.: 30 AF XY: 0.238 AC XY: 17634 AN XY: 74188

African (AFR) AF: 0.350 AC: 14489 AN: 41344

American (AMR) AF: 0.260 AC: 3960 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 808 AN: 3470

East Asian (EAS) AF: 0.367 AC: 1876 AN: 5118

South Asian (SAS) AF: 0.214 AC: 1028 AN: 4810

European-Finnish (FIN) AF: 0.222 AC: 2340 AN: 10560

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10385 AN: 67948

Other (OTH) AF: 0.225 AC: 476 AN: 2112

Alfa AF: 0.217 Hom.: 639

Bravo AF: 0.245

Asia WGS AF: 0.279 AC: 970 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.81
DANN	Benign	0.43
PhyloP100		0.15
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: rs3757933; hg19: chr8-32604843;