6-131675155-G-T

Position:

• chr6-131675155-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005021.5(ENPP3):​c.838G>T​(p.Gly280Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENPP3 NM_005021.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP3	NM_005021.5	c.838G>T	p.Gly280Cys	missense_variant	9/25	ENST00000357639.8	NP_005012.2
ENPP3	XM_017010932.2	c.607G>T	p.Gly203Cys	missense_variant	7/23		XP_016866421.1
ENPP3	XM_011535897.2	c.76G>T	p.Gly26Cys	missense_variant	2/18		XP_011534199.1
ENPP3	NR_133007.2	n.921G>T		non_coding_transcript_exon_variant	9/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP3	ENST00000357639.8	c.838G>T	p.Gly280Cys	missense_variant	9/25	1	NM_005021.5	ENSP00000350265.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Oct 30, 2024

The c.838G>T (p.G280C) alteration is located in exon 9 (coding exon 9) of the ENPP3 gene. This alteration results from a G to T substitution at nucleotide position 838, causing the glycine (G) at amino acid position 280 to be replaced by a cysteine (C). 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	0.35
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.9	H;H;.
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.64
MutPred		0.74		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.90
MPC		0.38
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.80
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: chr6-131996295;