rs1362113335

Variant names:

• chr10-81875426-C-A
• rs1362113335
• NM_001010848.4:c.86C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001010848.4(NRG3):​c.86C>A​(p.Ala29Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,098,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NRG3 NM_001010848.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.437
• Publications: 1 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]

ENSG00000287358 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062307954).

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.86C>A	p.Ala29Glu	missense	Exon 1 of 9	NP_001010848.2	P56975-4
	NRG3	NM_001370084.1		c.86C>A	p.Ala29Glu	missense	Exon 1 of 10	NP_001357013.1	D9ZHP6
	NRG3	NM_001370081.1		c.86C>A	p.Ala29Glu	missense	Exon 1 of 9	NP_001357010.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG3	ENST00000372141.7	TSL:1 MANE Select	c.86C>A	p.Ala29Glu	missense	Exon 1 of 9	ENSP00000361214.2	P56975-4
	NRG3	ENST00000404547.5	TSL:1	c.86C>A	p.Ala29Glu	missense	Exon 1 of 10	ENSP00000384796.1	P56975-1
	ENSG00000287358	ENST00000821630.1		n.183+617G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 2 AN: 952572 Hom.: 0 Cov.: 30 AF XY: 0.00000447 AC XY: 2 AN XY: 447838

African (AFR) AF: 0.000107 AC: 2 AN: 18772

American (AMR) AF: 0.00 AC: 0 AN: 4418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8982

East Asian (EAS) AF: 0.00 AC: 0 AN: 13414

South Asian (SAS) AF: 0.00 AC: 0 AN: 18472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2504

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838804

Other (OTH) AF: 0.00 AC: 0 AN: 34628

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146200 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 1 AN XY: 71120

African (AFR) AF: 0.0000492 AC: 2 AN: 40638

American (AMR) AF: 0.00 AC: 0 AN: 14774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 4840

South Asian (SAS) AF: 0.00 AC: 0 AN: 4648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65882

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	22
DANN	Benign	0.83
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.44
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.81	N
REVEL	Benign	0.044
Sift	Benign	1.0	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.40	B
Vest4		0.26
MutPred		0.30		Loss of helix (P = 0.0444)
MVP		0.20
MPC		0.65
ClinPred		0.083	T
GERP RS		0.72
PromoterAI		-0.0042	Neutral
Varity_R		0.11
gMVP		0.26
Mutation Taster		=97/3	polymorphism

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: rs1362113335; hg19: chr10-83635182;