10-82985170-C-A

Position:

• chr10-82985170-C-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
NRG3	NM_001010848.4	c.1656C>A	p.Asn552Lys	missense_variant	9/9	ENST00000372141.7	NP_001010848.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRG3	ENST00000372141.7	c.1656C>A	p.Asn552Lys	missense_variant	9/9	1	NM_001010848.4	ENSP00000361214	A2

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

GnomAD3 exomes AF: 0.0791 AC: 19866 AN: 251230 Hom.: 1186 AF XY: 0.0745 AC XY: 10111 AN XY: 135788

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 SAS exome AF: 0.0770

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

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.0482

Gnomad4 EAS exome AF: 0.0269

Gnomad4 SAS exome AF: 0.0782

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.0639

Gnomad4 OTH exome AF: 0.0728

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

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0461

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.0766

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.0621

Gnomad4 OTH AF: 0.0810

Alfa AF: 0.0677 Hom.: 735

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;.;.;.;.;.
MutationTaster	Benign	0.90	P;P;P;P;P;P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17101193; hg19: chr10-84744926;