8-32750356-T-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013964.5	c.701-4016T>G		intron_variant		ENST00000405005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000405005.8	c.701-4016T>G		intron_variant		1	NM_013964.5	A2

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

Gnomad4 AFR AF: 0.0850

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.0983

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.111

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.64
Dann	Benign	0.68

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4512342; hg19: chr8-32607874;