6-131671268-A-G

Position:

• chr6-131671268-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005021.5(ENPP3):​c.583A>G​(p.Lys195Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ENPP3 NM_005021.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.552

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27126133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP3	NM_005021.5	c.583A>G	p.Lys195Glu	missense_variant	7/25	ENST00000357639.8	NP_005012.2
ENPP3	XM_017010932.2	c.352A>G	p.Lys118Glu	missense_variant	5/23		XP_016866421.1
ENPP3	NR_133007.2	n.666A>G		non_coding_transcript_exon_variant	7/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP3	ENST00000357639.8	c.583A>G	p.Lys195Glu	missense_variant	7/25	1	NM_005021.5	ENSP00000350265.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447534 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 721148

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Aug 20, 2024

The c.583A>G (p.K195E) alteration is located in exon 7 (coding exon 7) of the ENPP3 gene. This alteration results from a A to G substitution at nucleotide position 583, causing the lysine (K) at amino acid position 195 to be replaced by a glutamic acid (E). 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	Benign	0.10
BayesDel_addAF	Benign	0.0025	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	.;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.033	D;D;D
Sift4G	Uncertain	0.055	T;T;T
Polyphen		0.011	B;B;.
Vest4		0.39
MutPred		0.55		Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);
MVP		0.60
MPC		0.11
ClinPred		0.49	T
GERP RS		-0.31
Varity_R		0.24
gMVP		0.78

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: chr6-131992408;