10-82724221-C-T

Variant names:

• chr10-82724221-C-T
• rs2249075
• NM_001010848.4:c.954-14356C>T

Variant summary

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

The NM_001010848.4(NRG3):​c.954-14356C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 149,994 control chromosomes in the GnomAD database, including 55,523 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 0.86 (55523 hom., cov: 29)
• Consequence: NRG3 NM_001010848.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.789
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.891 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.954-14356C>T		intron	N/A	NP_001010848.2
	NRG3	NM_001370084.1		c.954-14356C>T		intron	N/A	NP_001357013.1
	NRG3	NM_001370081.1		c.954-14356C>T		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.954-14356C>T		intron	N/A	ENSP00000361214.2
	NRG3	ENST00000404547.5	TSL:1	c.954-14356C>T		intron	N/A	ENSP00000384796.1
	NRG3	ENST00000556918.5	TSL:1	c.444-14356C>T		intron	N/A	ENSP00000451376.1

Frequencies

GnomAD3 genomes AF: 0.861 AC: 129088 AN: 149914 Hom.: 55484 Cov.: 29

Gnomad AFR AF: 0.899

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.879

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.877

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.850

Gnomad MID AF: 0.856

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.868

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

GnomAD4 genome AF: 0.861 AC: 129169 AN: 149994 Hom.: 55523 Cov.: 29 AF XY: 0.860 AC XY: 62942 AN XY: 73164

African (AFR) AF: 0.899 AC: 36811 AN: 40962

American (AMR) AF: 0.880 AC: 13262 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2954 AN: 3454

East Asian (EAS) AF: 0.878 AC: 4486 AN: 5108

South Asian (SAS) AF: 0.820 AC: 3900 AN: 4758

European-Finnish (FIN) AF: 0.850 AC: 8498 AN: 10000

Middle Eastern (MID) AF: 0.853 AC: 244 AN: 286

European-Non Finnish (NFE) AF: 0.839 AC: 56520 AN: 67386

Other (OTH) AF: 0.869 AC: 1785 AN: 2054

Alfa AF: 0.852 Hom.: 78220

Bravo AF: 0.869

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.7
DANN	Benign	0.41
PhyloP100		-0.79
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: rs2249075; hg19: chr10-84483977;