6-131685441-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005021.5(ENPP3):c.1198G>A(p.Glu400Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: ENPP3 NM_005021.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.159

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15194184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP3	NM_005021.5	c.1198G>A	p.Glu400Lys	missense_variant	13/25	ENST00000357639.8
ENPP3	XM_017010932.2	c.967G>A	p.Glu323Lys	missense_variant	11/23
ENPP3	XM_011535897.2	c.436G>A	p.Glu146Lys	missense_variant	6/18
ENPP3	NR_133007.2	n.1281G>A		non_coding_transcript_exon_variant	13/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP3	ENST00000357639.8	c.1198G>A	p.Glu400Lys	missense_variant	13/25	1	NM_005021.5	P1
ENPP3	ENST00000414305.5	c.1198G>A	p.Glu400Lys	missense_variant	14/26	1		P1
ENPP3	ENST00000358229.6	c.1198G>A	p.Glu400Lys	missense_variant	13/24	1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151938 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000876 AC: 22 AN: 251278 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135820

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461692 Hom.: 0 Cov.: 30 AF XY: 0.0000440 AC XY: 32 AN XY: 727170

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151938 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74210

Gnomad4 AFR AF: 0.000363

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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 30, 2022

The c.1198G>A (p.E400K) alteration is located in exon 13 (coding exon 13) of the ENPP3 gene. This alteration results from a G to A substitution at nucleotide position 1198, causing the glutamic acid (E) at amino acid position 400 to be replaced by a lysine (K). 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	0.27
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.070	T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.81	P;P;.
Vest4		0.40
MVP		0.67
MPC		0.17
ClinPred		0.071	T
GERP RS		1.6
Varity_R		0.15
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs141972191; hg19: chr6-132006581; COSMIC: COSV62955381;