rs192954755

Positions:

• chr10-95755766-G-A
• chr10-95755766-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164178.1(ENTPD1):​c.52G>A​(p.Glu18Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,536,624 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (34 hom.)
• Consequence: ENTPD1 NM_001164178.1 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.33

Genes affected

ENTPD1 (HGNC:3363): (ectonucleoside triphosphate diphosphohydrolase 1) The protein encoded by this gene is a plasma membrane protein that hydrolyzes extracellular ATP and ADP to AMP. Inhibition of this protein's activity may confer anticancer benefits. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

ENTPD1-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003439933).
• BP6: Variant 10-95755766-G-A is Benign according to our data. Variant chr10-95755766-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547899.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr10-95755766-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00481 (732/152272) while in subpopulation NFE AF= 0.00482 (328/68028). AF 95% confidence interval is 0.00439. There are 3 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENTPD1	NM_001164178.1	c.52G>A	p.Glu18Lys	missense_variant, splice_region_variant	1/10		NP_001157650.1
ENTPD1	NM_001320916.1	c.52G>A	p.Glu18Lys	missense_variant, splice_region_variant	1/10		NP_001307845.1
ENTPD1	NM_001164181.1	c.-181G>A		splice_region_variant	1/9		NP_001157653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENTPD1	ENST00000453258.6	c.37+43773G>A		intron_variant		1		ENSP00000390955.2
ENTPD1	ENST00000371207.8	c.52G>A	p.Glu18Lys	missense_variant, splice_region_variant	1/10	2		ENSP00000360250.3
ENTPD1	ENST00000543964.6	c.-181G>A		splice_region_variant	1/9	2		ENSP00000442968.1

Frequencies

GnomAD3 genomes AF: 0.00482 AC: 733 AN: 152154 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0306

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00482

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00335 AC: 475 AN: 141932 Hom.: 3 AF XY: 0.00333 AC XY: 253 AN XY: 75902

Gnomad AFR exome AF: 0.000921

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000220

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.00494

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00616 AC: 8528 AN: 1384352 Hom.: 34 Cov.: 30 AF XY: 0.00601 AC XY: 4106 AN XY: 683206

Gnomad4 AFR exome AF: 0.000918

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.0000794

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000303

Gnomad4 FIN exome AF: 0.0209

Gnomad4 NFE exome AF: 0.00682

Gnomad4 OTH exome AF: 0.00599

GnomAD4 genome AF: 0.00481 AC: 732 AN: 152272 Hom.: 3 Cov.: 32 AF XY: 0.00583 AC XY: 434 AN XY: 74450

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0306

Gnomad4 NFE AF: 0.00482

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00381 Hom.: 2

Bravo AF: 0.00270

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00409 AC: 13

ExAC AF: 0.00114 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ENTPD1: PP3, BS2; ENTPD1-AS1: BS2 -

Hereditary spastic paraplegia 64 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 29, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.031
Sift	Benign	0.072	T
Sift4G	Benign	0.094	T
Vest4		0.20
MVP		0.13
MPC		0.18
ClinPred		0.0058	T
GERP RS		3.0
gMVP		0.36

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs192954755; hg19: chr10-97515523;