Genetic Variant ENPP3:p.Met35Thr (chr6-131641480-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005021.5(ENPP3):c.104T>C(p.Met35Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,612,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ENPP3
NM_005021.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.44

Publications

0 publications found

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.061547756).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005021.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP3	NM_005021.5	MANE Select	c.104T>C	p.Met35Thr	missense	Exon 2 of 25	NP_005012.2	O14638
	ENPP3	NR_133007.2		n.187T>C		non_coding_transcript_exon	Exon 2 of 24

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENPP3	ENST00000357639.8	TSL:1 MANE Select	c.104T>C	p.Met35Thr	missense	Exon 2 of 25	ENSP00000350265.3	O14638
ENPP3	ENST00000414305.5	TSL:1	c.104T>C	p.Met35Thr	missense	Exon 3 of 26	ENSP00000406261.1	O14638
ENPP3	ENST00000427707.5	TSL:1	n.*68T>C		non_coding_transcript_exon	Exon 4 of 12	ENSP00000415589.1	E7ETI7

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000876

AC:

AN:

251180

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1460102

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

726434

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.000425

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110694

Other (OTH)

AF:

0.000116

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00118

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.047

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.57

M_CAP

Benign

0.018

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

4.4

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.49

REVEL

Benign

0.12

Sift

Benign

0.75

Sift4G

Benign

0.59

Polyphen

0.0040

Vest4

0.33

MutPred

0.37

Loss of stability (P = 0.0016)

MVP

0.37

MPC

0.072

ClinPred

0.049

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.43

Mutation Taster

=54/145

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over