rs4298457

chr8-32585856-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.101-9972T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,006 control chromosomes in the GnomAD database, including 5,109 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 0.26 (5109 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.384

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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013964.5	c.101-9972T>G		intron_variant		ENST00000405005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000405005.8	c.101-9972T>G		intron_variant		1	NM_013964.5	A2

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38898 AN: 151888 Hom.: 5105 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.245

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

GnomAD4 genome AF: 0.256 AC: 38926 AN: 152006 Hom.: 5109 Cov.: 32 AF XY: 0.257 AC XY: 19086 AN XY: 74290

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.325

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.243

Alfa AF: 0.268 Hom.: 2506

Bravo AF: 0.243

Asia WGS AF: 0.273 AC: 950 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.47
Dann	Benign	0.29

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4298457; hg19: chr8-32443374;