10-82985170-C-A

Variant names:

• chr10-82985170-C-A
• rs17101193
• NM_001010848.4:c.1656C>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.1656C>A​(p.Asn552Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0701 in 1,613,980 control chromosomes in the GnomAD database, including 4,979 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.090 (816 hom., cov: 32)
  • Exomes 𝑓: 0.068 (4163 hom.)
• Consequence: NRG3 NM_001010848.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.243
• Publications: 17 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 (MetaRNN=0.0016068518).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG3	NM_001010848.4	c.1656C>A	p.Asn552Lys	missense_variant	Exon 9 of 9	ENST00000372141.7	NP_001010848.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG3	ENST00000372141.7	c.1656C>A	p.Asn552Lys	missense_variant	Exon 9 of 9	1	NM_001010848.4	ENSP00000361214.2

Frequencies

GnomAD3 genomes AF: 0.0904 AC: 13750 AN: 152040 Hom.: 813 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.0776

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.0809

GnomAD2 exomes AF: 0.0791 AC: 19866 AN: 251230 AF XY: 0.0745

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.0518

Gnomad EAS exome AF: 0.0180

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0607

Gnomad OTH exome AF: 0.0822

GnomAD4 exome AF: 0.0680 AC: 99335 AN: 1461822 Hom.: 4163 Cov.: 31 AF XY: 0.0669 AC XY: 48687 AN XY: 727222

African (AFR) AF: 0.153 AC: 5131 AN: 33478

American (AMR) AF: 0.178 AC: 7960 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0482 AC: 1260 AN: 26136

East Asian (EAS) AF: 0.0269 AC: 1068 AN: 39700

South Asian (SAS) AF: 0.0782 AC: 6747 AN: 86258

European-Finnish (FIN) AF: 0.0236 AC: 1262 AN: 53418

Middle Eastern (MID) AF: 0.0884 AC: 510 AN: 5768

European-Non Finnish (NFE) AF: 0.0639 AC: 71003 AN: 1111946

Other (OTH) AF: 0.0728 AC: 4394 AN: 60394

GnomAD4 genome AF: 0.0904 AC: 13758 AN: 152158 Hom.: 816 Cov.: 32 AF XY: 0.0875 AC XY: 6511 AN XY: 74386

African (AFR) AF: 0.154 AC: 6390 AN: 41498

American (AMR) AF: 0.134 AC: 2050 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3468

East Asian (EAS) AF: 0.0189 AC: 98 AN: 5174

South Asian (SAS) AF: 0.0766 AC: 369 AN: 4818

European-Finnish (FIN) AF: 0.0187 AC: 198 AN: 10598

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0621 AC: 4222 AN: 68010

Other (OTH) AF: 0.0810 AC: 171 AN: 2112

Alfa AF: 0.0701 Hom.: 1567

Bravo AF: 0.103

TwinsUK AF: 0.0658 AC: 244

ALSPAC AF: 0.0711 AC: 274

ESP6500AA AF: 0.155 AC: 682

ESP6500EA AF: 0.0580 AC: 499

ExAC AF: 0.0764 AC: 9279

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.0623

EpiControl AF: 0.0650

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.24	.;T;.;T;T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.77	T;T;T;T;T;T;.
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.35	.;N;.;.;.;.;.
PhyloP100		-0.24
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.15	T;T;T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;.;.;.;.
Vest4		0.23
MutPred		0.13		.;Gain of ubiquitination at N576 (P = 0.0101);.;.;.;.;.;
MPC		0.099
ClinPred		0.0045	T
GERP RS		2.7
Varity_R		0.076
gMVP		0.31
Mutation Taster		=99/1	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: rs17101193; hg19: chr10-84744926; COSMIC: COSV107462349;