6-131637451-A-G

Position:

• chr6-131637451-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005021.5(ENPP3):​c.67A>G​(p.Ile23Val) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENPP3 NM_005021.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060634673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP3	NM_005021.5	c.67A>G	p.Ile23Val	missense_variant	1/25	ENST00000357639.8
ENPP3	NR_133007.2	n.150A>G		non_coding_transcript_exon_variant	1/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP3	ENST00000357639.8	c.67A>G	p.Ile23Val	missense_variant	1/25	1	NM_005021.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

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

Nov 10, 2022

The c.67A>G (p.I23V) alteration is located in exon 1 (coding exon 1) of the ENPP3 gene. This alteration results from a A to G substitution at nucleotide position 67, causing the isoleucine (I) at amino acid position 23 to be replaced by a valine (V). 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	0.083
BayesDel_addAF	Benign	-0.0025	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Benign	0.55
DEOGEN2	Benign	0.040	T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	0.77	D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.89	T;T;T
Polyphen		0.058	B;B;.
Vest4		0.11
MutPred		0.16		Loss of catalytic residue at L28 (P = 0.0394);Loss of catalytic residue at L28 (P = 0.0394);Loss of catalytic residue at L28 (P = 0.0394);
MVP		0.39
MPC		0.054
ClinPred		0.30	T
GERP RS		4.3
Varity_R		0.071
gMVP		0.43

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: chr6-131958591;