10-99709614-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020354.5(ENTPD7):c.*4931G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 985,316 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: ENTPD7 NM_020354.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.208

Genes affected

ENTPD7 (HGNC:19745): (ectonucleoside triphosphate diphosphohydrolase 7) This gene encodes a purine-converting ectoenzyme which belongs to the ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) family. The encoded protein hydrolyzes extracellular nucleoside triphosphates (UTP, GTP, and CTP) to nucleoside monophosphates as part of a purinergic signaling pathway. It contains two transmembrane domains at the N- and C-termini and a large, hydrophobic catalytic domain located in between. This gene affects oxidative stress as well as DNA damage and is a mediator of senescence. [provided by RefSeq, Mar 2017]

COX15 (HGNC:2263): (cytochrome c oxidase assembly homolog COX15) Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes a protein which is not a structural subunit, but may be essential for the biogenesis of COX formation and may function in the hydroxylation of heme O, according to the yeast mutant studies. This protein is predicted to contain 5 transmembrane domains localized in the mitochondrial inner membrane. Alternative splicing of this gene generates two transcript variants diverging in the 3' region. [provided by RefSeq, Jul 2008]

CUTC (HGNC:24271): (cutC copper transporter) Members of the CUT family of copper transporters are associated with copper homeostasis and are involved in the uptake, storage, delivery, and efflux of copper (Gupta et al., 1995 [PubMed 7635807]; Li et al., 2005 [PubMed 16182249]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENTPD7	NM_020354.5	c.*4931G>T		3_prime_UTR_variant	13/13	ENST00000370489.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENTPD7	ENST00000370489.5	c.*4931G>T		3_prime_UTR_variant	13/13	1	NM_020354.5	P1
CUTC	ENST00000493385.5	n.116+6941G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.000232 AC: 193 AN: 833082 Hom.: 1 Cov.: 30 AF XY: 0.000252 AC XY: 97 AN XY: 384706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.00175

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00395

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.000769

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74452

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000485 Hom.: 0

Bravo AF: 0.000370

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.77
Dann	Benign	0.59

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs576990987; hg19: chr10-101469371;