6-131677878-T-C

Position:

• chr6-131677878-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005021.5(ENPP3):​c.949T>C​(p.Tyr317His) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,453,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ENPP3 NM_005021.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

Genes affected

ENPP3 (HGNC:3358): (ectonucleotide pyrophosphatase/phosphodiesterase 3) The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Oct 2015]

ENPP3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP3	NM_005021.5	c.949T>C	p.Tyr317His	missense_variant	11/25	ENST00000357639.8	NP_005012.2
ENPP3	XM_017010932.2	c.718T>C	p.Tyr240His	missense_variant	9/23		XP_016866421.1
ENPP3	XM_011535897.2	c.187T>C	p.Tyr63His	missense_variant	4/18		XP_011534199.1
ENPP3	NR_133007.2	n.1032T>C		non_coding_transcript_exon_variant	11/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP3	ENST00000357639.8	c.949T>C	p.Tyr317His	missense_variant	11/25	1	NM_005021.5	ENSP00000350265.3
ENPP3	ENST00000414305.5	c.949T>C	p.Tyr317His	missense_variant	12/26	1		ENSP00000406261.1
ENPP3	ENST00000358229.6	c.949T>C	p.Tyr317His	missense_variant	11/24	1		ENSP00000350964.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1453474 Hom.: 0 Cov.: 27 AF XY: 0.0000111 AC XY: 8 AN XY: 723682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jul 10, 2023

The c.949T>C (p.Y317H) alteration is located in exon 11 (coding exon 11) of the ENPP3 gene. This alteration results from a T to C substitution at nucleotide position 949, causing the tyrosine (Y) at amino acid position 317 to be replaced by a histidine (H). 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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.075	D
MutationAssessor	Pathogenic	3.3	M;M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.4	D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.72		Gain of disorder (P = 0.0361);Gain of disorder (P = 0.0361);Gain of disorder (P = 0.0361);
MVP		0.75
MPC		0.42
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-131999018;