10-81876042-C-T

Position:

• chr10-81876042-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000372141.7(NRG3):​c.702C>T​(p.Tyr234=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,613,994 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (73 hom.)
• Consequence: NRG3 ENST00000372141.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.244

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-81876042-C-T is Benign according to our data. Variant chr10-81876042-C-T is described in ClinVar as [Benign]. Clinvar id is 770207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.244 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00344 (524/152320) while in subpopulation AMR AF= 0.0294 (450/15306). AF 95% confidence interval is 0.0272. There are 11 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRG3	NM_001010848.4	c.702C>T	p.Tyr234=	synonymous_variant	1/9	ENST00000372141.7	NP_001010848.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRG3	ENST00000372141.7	c.702C>T	p.Tyr234=	synonymous_variant	1/9	1	NM_001010848.4	ENSP00000361214	A2
NRG3	ENST00000404547.5	c.702C>T	p.Tyr234=	synonymous_variant	1/10	1		ENSP00000384796	A2

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152202 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00348

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00750 AC: 1873 AN: 249672 Hom.: 56 AF XY: 0.00568 AC XY: 768 AN XY: 135144

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.0505

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00337

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000802

Gnomad OTH exome AF: 0.00654

GnomAD4 exome AF: 0.00182 AC: 2667 AN: 1461674 Hom.: 73 Cov.: 32 AF XY: 0.00157 AC XY: 1143 AN XY: 727156

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.0506

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00494

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152320 Hom.: 11 Cov.: 32 AF XY: 0.00352 AC XY: 262 AN XY: 74480

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.0294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00349

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.000983 Hom.: 1

Bravo AF: 0.00639

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.8
DANN	Benign	0.88

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: rs76381424; hg19: chr10-83635798;