10-99709597-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_020354.5(ENTPD7):c.*4914T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 985,306 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.019 (26 hom., cov: 32)
  • Exomes 𝑓: 0.026 (265 hom.)
• Consequence: ENTPD7 NM_020354.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.969

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:):

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0186 (2839/152284) while in subpopulation NFE AF= 0.026 (1770/68018). AF 95% confidence interval is 0.025. There are 26 homozygotes in gnomad4. There are 1379 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENTPD7	NM_020354.5	c.*4914T>C		3_prime_UTR_variant	13/13	ENST00000370489.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENTPD7	ENST00000370489.5	c.*4914T>C		3_prime_UTR_variant	13/13	1	NM_020354.5	P1
CUTC	ENST00000493385.5	n.116+6924T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2842 AN: 152166 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0377

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0256 AC: 21367 AN: 833022 Hom.: 265 Cov.: 30 AF XY: 0.0256 AC XY: 9841 AN XY: 384664

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.0338

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.0326

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0204

GnomAD4 genome AF: 0.0186 AC: 2839 AN: 152284 Hom.: 26 Cov.: 32 AF XY: 0.0185 AC XY: 1379 AN XY: 74472

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.0377

Gnomad4 NFE AF: 0.0260

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0215 Hom.: 4

Bravo AF: 0.0168

Asia WGS AF: 0.00779 AC: 27 AN: 3478

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	-0.88
Cadd	Benign	3.5
Dann	Benign	0.71

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs76530337; hg19: chr10-101469354;