10-99708941-A-G

Variant names:

• chr10-99708941-A-G
• rs10490941
• NM_020354.5:c.*4258A>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.*4258A>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 0.00425 in 985,400 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (75 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (50 hom.)
• Consequence: ENTPD7 NM_020354.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.49

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]

ENSG00000285932 (HGNC:):

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=-0.81).
• BP6: Variant 10-99708941-A-G is Benign according to our data. Variant chr10-99708941-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 298362.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD7	NM_020354.5	c.*4258A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000370489.5	NP_065087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTPD7	ENST00000370489.5	c.*4258A>G		3_prime_UTR_variant	Exon 13 of 13	1	NM_020354.5	ENSP00000359520.4
ENSG00000285932	ENST00000649102.1	n.*460+7407T>C		intron_variant	Intron 8 of 12			ENSP00000497114.1
CUTC	ENST00000493385.5	n.116+6268A>G		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2831 AN: 152178 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.00163 AC: 1355 AN: 833104 Hom.: 50 Cov.: 30 AF XY: 0.00154 AC XY: 592 AN XY: 384714

Gnomad4 AFR exome AF: 0.0757

Gnomad4 AMR exome AF: 0.00305

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000608

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000932

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.0186 AC: 2834 AN: 152296 Hom.: 75 Cov.: 32 AF XY: 0.0172 AC XY: 1280 AN XY: 74468

Gnomad4 AFR AF: 0.0644

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0111 Hom.: 15

Bravo AF: 0.0210

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.4
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10490941; hg19: chr10-101468698;