10-81875515-G-C

Variant names:

• chr10-81875515-G-C
• rs1446835315
• NM_001010848.4:c.175G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001370082.1(NRG3):​c.-571G>C variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000274 in 1,458,602 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NRG3 NM_001370082.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28218043).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370082.1. 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.175G>C	p.Val59Leu	missense	Exon 1 of 9	NP_001010848.2	P56975-4
	NRG3	NM_001370082.1		c.-571G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001357011.1
	NRG3	NM_001370084.1		c.175G>C	p.Val59Leu	missense	Exon 1 of 10	NP_001357013.1	D9ZHP6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG3	ENST00000372141.7	TSL:1 MANE Select	c.175G>C	p.Val59Leu	missense	Exon 1 of 9	ENSP00000361214.2	P56975-4
	NRG3	ENST00000404547.5	TSL:1	c.175G>C	p.Val59Leu	missense	Exon 1 of 10	ENSP00000384796.1	P56975-1
	ENSG00000287358	ENST00000821630.1		n.183+528C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458602 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725454

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111058

Other (OTH) AF: 0.00 AC: 0 AN: 60274

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.5
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.043
Sift	Benign	0.078	T
Sift4G	Uncertain	0.018	D
Polyphen		0.46	P
Vest4		0.31
MutPred		0.29		Loss of catalytic residue at V59 (P = 0.0428)
MVP		0.42
MPC		1.4
ClinPred		0.60	D
GERP RS		2.6
PromoterAI		0.057	Neutral
Varity_R		0.19
gMVP		0.16
Mutation Taster		=71/29	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: rs1446835315; hg19: chr10-83635271;