10-99711101-C-CAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_020354.5(ENTPD7):c.*6425_*6426dup variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 974,650 control chromosomes in the GnomAD database, including 98 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0084 (7 hom., cov: 0)
  • Exomes 𝑓: 0.016 (91 hom.)
• Consequence: ENTPD7 NM_020354.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.217

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 -9 ACMG points.

• BP6: Variant 10-99711101-C-CAA is Benign according to our data. Variant chr10-99711101-C-CAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298386.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0156 (12802/822960) while in subpopulation NFE AF= 0.0161 (12135/752604). AF 95% confidence interval is 0.0159. There are 91 homozygotes in gnomad4_exome. There are 5957 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENTPD7	NM_020354.5	c.*6425_*6426dup		3_prime_UTR_variant	13/13	ENST00000370489.5
COX15	NM_078470.6	c.*3485_*3486insTT		3_prime_UTR_variant	9/9	ENST00000016171.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX15	ENST00000016171.6	c.*3485_*3486insTT		3_prime_UTR_variant	9/9	1	NM_078470.6	P1
ENTPD7	ENST00000370489.5	c.*6425_*6426dup		3_prime_UTR_variant	13/13	1	NM_020354.5	P1
CUTC	ENST00000493385.5	n.116+8435_116+8436dup		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00837 AC: 1269 AN: 151576 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.00269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.00956

Gnomad FIN AF: 0.00510

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.0156 AC: 12802 AN: 822960 Hom.: 91 Cov.: 30 AF XY: 0.0157 AC XY: 5957 AN XY: 380182

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00453

Gnomad4 EAS exome AF: 0.000556

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.00365

Gnomad4 NFE exome AF: 0.0161

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.00835 AC: 1267 AN: 151690 Hom.: 7 Cov.: 0 AF XY: 0.00800 AC XY: 593 AN XY: 74092

Gnomad4 AFR AF: 0.00268

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.00915

Gnomad4 FIN AF: 0.00510

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00572 Hom.: 1702

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

COX15: BS1, BS2; ENTPD7: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11405417; hg19: chr10-101470858;