chr20-25207368-A-C

Position:

• chr20-25207368-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001247.5(ENTPD6):​c.347A>C​(p.His116Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ENTPD6 NM_001247.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90

Genes affected

ENTPD6 (HGNC:3368): (ectonucleoside triphosphate diphosphohydrolase 6) ENTPD6 is similar to E-type nucleotidases (NTPases). NTPases, such as CD39, mediate catabolism of extracellular nucleotides. ENTPD6 contains 4 apyrase-conserved regions which are characteristic of NTPases. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENTPD6	NM_001247.5	c.347A>C	p.His116Pro	missense_variant	3/15	ENST00000376652.9	NP_001238.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENTPD6	ENST00000376652.9	c.347A>C	p.His116Pro	missense_variant	3/15	1	NM_001247.5	ENSP00000365840	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.347A>C (p.H116P) alteration is located in exon 3 (coding exon 2) of the ENTPD6 gene. This alteration results from a A to C substitution at nucleotide position 347, causing the histidine (H) at amino acid position 116 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	.;.;T;.;T;T;.;T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.032	D
MutationAssessor	Pathogenic	4.1	.;.;H;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-8.6	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.011	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.061	T;T;T;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D;.;.;.
Vest4		0.96
MutPred		0.84		.;.;Gain of glycosylation at T113 (P = 0.05);.;.;Gain of glycosylation at T113 (P = 0.05);.;.;Gain of glycosylation at T113 (P = 0.05);
MVP		0.44
MPC		1.1
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2091589346; hg19: chr20-25188004;