rs2219937

Variant names:

• chr10-82659654-G-A
• rs2219937
• NM_001010848.4:c.954-78923G>A

Variant summary

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

The NM_001010848.4(NRG3):​c.954-78923G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0747 in 151,652 control chromosomes in the GnomAD database, including 1,104 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 0.075 (1104 hom., cov: 32)
• Consequence: NRG3 NM_001010848.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• Publications: 3 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG3	NM_001010848.4	MANE Select	c.954-78923G>A		intron	N/A	NP_001010848.2
	NRG3	NM_001370084.1		c.954-78923G>A		intron	N/A	NP_001357013.1
	NRG3	NM_001370081.1		c.954-78923G>A		intron	N/A	NP_001357010.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG3	ENST00000372141.7	TSL:1 MANE Select	c.954-78923G>A		intron	N/A	ENSP00000361214.2
	NRG3	ENST00000404547.5	TSL:1	c.954-78923G>A		intron	N/A	ENSP00000384796.1
	NRG3	ENST00000556918.5	TSL:1	c.444-78923G>A		intron	N/A	ENSP00000451376.1

Frequencies

GnomAD3 genomes AF: 0.0747 AC: 11323 AN: 151536 Hom.: 1102 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.0347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.00361

Gnomad MID AF: 0.0481

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0607

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

GnomAD4 genome AF: 0.0747 AC: 11334 AN: 151652 Hom.: 1104 Cov.: 32 AF XY: 0.0724 AC XY: 5366 AN XY: 74082

African (AFR) AF: 0.230 AC: 9510 AN: 41280

American (AMR) AF: 0.0289 AC: 440 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 120 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.0313 AC: 150 AN: 4794

European-Finnish (FIN) AF: 0.00361 AC: 38 AN: 10526

Middle Eastern (MID) AF: 0.0517 AC: 15 AN: 290

European-Non Finnish (NFE) AF: 0.0138 AC: 935 AN: 67934

Other (OTH) AF: 0.0601 AC: 126 AN: 2098

Alfa AF: 0.0556 Hom.: 102

Bravo AF: 0.0827

Asia WGS AF: 0.0240 AC: 86 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.80
DANN	Benign	0.55
PhyloP100		-0.54
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: rs2219937; hg19: chr10-84419410;