10-99711170-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020354.5(ENTPD7):c.*6487A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 984,884 control chromosomes in the GnomAD database, including 6,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (1004 hom., cov: 32)
  • Exomes 𝑓: 0.11 (5348 hom.)
• Consequence: ENTPD7 NM_020354.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.274

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-99711170-A-G is Benign according to our data. Variant chr10-99711170-A-G is described in ClinVar as [Benign]. Clinvar id is 298387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENTPD7	NM_020354.5	c.*6487A>G		3_prime_UTR_variant	13/13	ENST00000370489.5
COX15	NM_078470.6	c.*3417T>C		3_prime_UTR_variant	9/9	ENST00000016171.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX15	ENST00000016171.6	c.*3417T>C		3_prime_UTR_variant	9/9	1	NM_078470.6	P1
ENTPD7	ENST00000370489.5	c.*6487A>G		3_prime_UTR_variant	13/13	1	NM_020354.5	P1
CUTC	ENST00000493385.5	n.116+8497A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15569 AN: 152124 Hom.: 1000 Cov.: 32

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.0994

Gnomad ASJ AF: 0.0876

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0958

GnomAD4 exome AF: 0.111 AC: 92186 AN: 832642 Hom.: 5348 Cov.: 31 AF XY: 0.111 AC XY: 42606 AN XY: 384518

Gnomad4 AFR exome AF: 0.0526

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.0806

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.102 AC: 15578 AN: 152242 Hom.: 1004 Cov.: 32 AF XY: 0.105 AC XY: 7794 AN XY: 74426

Gnomad4 AFR AF: 0.0565

Gnomad4 AMR AF: 0.0994

Gnomad4 ASJ AF: 0.0876

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.0962

Alfa AF: 0.107 Hom.: 128

Bravo AF: 0.100

Asia WGS AF: 0.198 AC: 686 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.6
Dann	Benign	0.84

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10883407; hg19: chr10-101470927;