10-81876028-G-T

Variant names:

• chr10-81876028-G-T
• rs200553274
• NM_001010848.4:c.688G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001010848.4(NRG3):​c.688G>T​(p.Ala230Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,613,768 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: NRG3 NM_001010848.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65
• Publications: 4 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01492244).

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.688G>T	p.Ala230Ser	missense	Exon 1 of 9	NP_001010848.2	P56975-4
	NRG3	NM_001370084.1		c.688G>T	p.Ala230Ser	missense	Exon 1 of 10	NP_001357013.1	D9ZHP6
	NRG3	NM_001370081.1		c.688G>T	p.Ala230Ser	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.688G>T	p.Ala230Ser	missense	Exon 1 of 9	ENSP00000361214.2	P56975-4
	NRG3	ENST00000404547.5	TSL:1	c.688G>T	p.Ala230Ser	missense	Exon 1 of 10	ENSP00000384796.1	P56975-1
	ENSG00000287358	ENST00000821630.1		n.183+15C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000208 AC: 52 AN: 250048 AF XY: 0.000229

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461648 Hom.: 1 Cov.: 32 AF XY: 0.000125 AC XY: 91 AN XY: 727162

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53202

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000719 AC: 80 AN: 1112008

Other (OTH) AF: 0.000215 AC: 13 AN: 60386

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000235 Hom.: 1

Bravo AF: 0.000132

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

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	0.098
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.026
Sift	Benign	0.39	T
Sift4G	Benign	0.62	T
Polyphen		0.052	B
Vest4		0.15
MVP		0.30
MPC		0.56
ClinPred		0.020	T
GERP RS		3.1
Varity_R		0.081
gMVP		0.26
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200553274; hg19: chr10-83635784;