chr8-32750356-T-G

Variant names:

• chr8-32750356-T-G
• rs4512342
• NM_013964.5:c.701-4016T>G

Variant summary

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

The NM_013964.5(NRG1):​c.701-4016T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,126 control chromosomes in the GnomAD database, including 1,590 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 0.13 (1590 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.200
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013964.5. 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_013964.5	MANE Select	c.701-4016T>G		intron	N/A	NP_039258.1
	NRG1	NM_001322205.2		c.880+772T>G		intron	N/A	NP_001309134.1
	NRG1	NM_013956.5		c.715+772T>G		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.701-4016T>G		intron	N/A	ENSP00000384620.2
	NRG1	ENST00000287842.7	TSL:1	c.715+772T>G		intron	N/A	ENSP00000287842.4
	NRG1	ENST00000356819.7	TSL:1	c.692-4016T>G		intron	N/A	ENSP00000349275.6

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19551 AN: 152008 Hom.: 1591 Cov.: 32

Gnomad AFR AF: 0.0851

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0983

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.113

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

GnomAD4 genome AF: 0.129 AC: 19549 AN: 152126 Hom.: 1590 Cov.: 32 AF XY: 0.136 AC XY: 10092 AN XY: 74364

African (AFR) AF: 0.0850 AC: 3532 AN: 41530

American (AMR) AF: 0.193 AC: 2950 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0983 AC: 341 AN: 3470

East Asian (EAS) AF: 0.370 AC: 1906 AN: 5152

South Asian (SAS) AF: 0.150 AC: 721 AN: 4822

European-Finnish (FIN) AF: 0.196 AC: 2072 AN: 10550

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7658 AN: 67998

Other (OTH) AF: 0.111 AC: 235 AN: 2114

Alfa AF: 0.117 Hom.: 169

Bravo AF: 0.130

Asia WGS AF: 0.222 AC: 773 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.64
DANN	Benign	0.68
PhyloP100		-0.20
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: rs4512342; hg19: chr8-32607874;