rs8421

Positions:

• chr10-82986865-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001010848.4(NRG3):​c.*1260A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 152,100 control chromosomes in the GnomAD database, including 16,612 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 0.45 (16612 hom., cov: 33)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: NRG3 NM_001010848.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68

Genes affected

NRG3 (HGNC:7999): (neuregulin 3) This gene is a member of the neuregulin gene family. This gene family encodes ligands for the transmembrane tyrosine kinase receptors ERBB3 and ERBB4 - members of the epidermal growth factor receptor family. Ligand binding activates intracellular signaling cascades and the induction of cellular responses including proliferation, migration, differentiation, and survival or apoptosis. This gene encodes neuregulin 3 (NRG3). NRG3 has been shown to activate the tyrosine phosphorylation of its cognate receptor, ERBB4, and is thought to influence neuroblast proliferation, migration and differentiation by signalling through ERBB4. NRG3 also promotes mammary differentiation during embryogenesis. Linkage studies have implicated this gene as a susceptibility locus for schizophrenia and schizoaffective disorder. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but their biological validity has not been verified.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG3	NM_001010848.4	c.*1260A>G		3_prime_UTR_variant	9/9	ENST00000372141.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG3	ENST00000372141.7	c.*1260A>G		3_prime_UTR_variant	9/9	1	NM_001010848.4	A2
NRG3	ENST00000372142.6	c.*1260A>G		3_prime_UTR_variant	11/11	1		A2
NRG3	ENST00000545131.5	c.*1260A>G		3_prime_UTR_variant	7/7	5
NRG3	ENST00000602794.5	c.*2987A>G		3_prime_UTR_variant, NMD_transcript_variant	11/11	2

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67825 AN: 151978 Hom.: 16612 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.487

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.446 AC: 67844 AN: 152096 Hom.: 16612 Cov.: 33 AF XY: 0.439 AC XY: 32683 AN XY: 74378

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.417

Gnomad4 ASJ AF: 0.581

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.407

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.572

Gnomad4 OTH AF: 0.487

Alfa AF: 0.544 Hom.: 38389

Bravo AF: 0.436

Asia WGS AF: 0.330 AC: 1144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs8421; hg19: chr10-84746621;