10-81875637-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001010848.4(NRG3):c.297C>T(p.Pro99=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 1,613,846 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: NRG3 NM_001010848.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0780

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-81875637-C-T is Benign according to our data. Variant chr10-81875637-C-T is described in ClinVar as [Benign]. Clinvar id is 716399.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.078 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG3	NM_001010848.4	c.297C>T	p.Pro99=	synonymous_variant	1/9	ENST00000372141.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG3	ENST00000372141.7	c.297C>T	p.Pro99=	synonymous_variant	1/9	1	NM_001010848.4	A2
NRG3	ENST00000404547.5	c.297C>T	p.Pro99=	synonymous_variant	1/10	1		A2

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 404 AN: 152056 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000954 AC: 239 AN: 250586 Hom.: 0 AF XY: 0.000811 AC XY: 110 AN XY: 135650

Gnomad AFR exome AF: 0.00914

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000471 AC: 689 AN: 1461672 Hom.: 1 Cov.: 32 AF XY: 0.000447 AC XY: 325 AN XY: 727146

Gnomad4 AFR exome AF: 0.00818

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000239

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.00264 AC: 401 AN: 152174 Hom.: 1 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74408

Gnomad4 AFR AF: 0.00869

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000870 Hom.: 0

Bravo AF: 0.00314

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Benign	0.94

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: rs147245216; hg19: chr10-83635393;