rs474018

Variant names:

• chr10-82854330-A-G
• rs474018
• NM_001010848.4:c.1028-11081A>G

Variant summary

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

The NM_001010848.4(NRG3):​c.1028-11081A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 151,974 control chromosomes in the GnomAD database, including 16,300 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 0.46 (16300 hom., cov: 31)
• Consequence: NRG3 NM_001010848.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010848.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG3	NM_001010848.4	MANE Select	c.1028-11081A>G		intron	N/A	NP_001010848.2	P56975-4
	NRG3	NM_001370084.1		c.1028-11081A>G		intron	N/A	NP_001357013.1	D9ZHP6
	NRG3	NM_001370081.1		c.1028-11084A>G		intron	N/A	NP_001357010.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG3	ENST00000372141.7	TSL:1 MANE Select	c.1028-11081A>G		intron	N/A	ENSP00000361214.2	P56975-4
	NRG3	ENST00000404547.5	TSL:1	c.1028-11081A>G		intron	N/A	ENSP00000384796.1	P56975-1
	NRG3	ENST00000556918.5	TSL:1	c.518-11081A>G		intron	N/A	ENSP00000451376.1	D9ZHQ7

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69637 AN: 151858 Hom.: 16292 Cov.: 31

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.458 AC: 69672 AN: 151974 Hom.: 16300 Cov.: 31 AF XY: 0.452 AC XY: 33600 AN XY: 74284

African (AFR) AF: 0.482 AC: 19970 AN: 41436

American (AMR) AF: 0.382 AC: 5834 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1718 AN: 3472

East Asian (EAS) AF: 0.127 AC: 655 AN: 5164

South Asian (SAS) AF: 0.456 AC: 2196 AN: 4812

European-Finnish (FIN) AF: 0.427 AC: 4513 AN: 10570

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.494 AC: 33533 AN: 67946

Other (OTH) AF: 0.442 AC: 932 AN: 2108

Alfa AF: 0.452 Hom.: 2796

Bravo AF: 0.452

Asia WGS AF: 0.299 AC: 1044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	6.0
DANN	Benign	0.74
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs474018; hg19: chr10-84614086;