Variant 6-131808037-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006208.3(ENPP1):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000432 in 694,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 16)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

ENPP1
NM_006208.3 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.458

Variant links:

Genes affected

ENPP1 (HGNC:3356): (ectonucleotide pyrophosphatase/phosphodiesterase 1) This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with 'idiopathic' infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. [provided by RefSeq, Jul 2008]

ENPP1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-131808037-T-G is Pathogenic according to our data. Variant chr6-131808037-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3593042.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3 link	c.2T>G	p.Met1?	start_lost	1/25	ENST00000647893.1	NP_006199.2	P22413

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ENPP1	ENST00000647893.1 link	c.2T>G	p.Met1?	start_lost	1/25		NM_006208.3	ENSP00000498074.1	P22413
ENPP1	ENST00000486853.1 link	n.22T>G		non_coding_transcript_exon_variant	1/4	2
ENPP1	ENST00000513998.5 link	n.2T>G		non_coding_transcript_exon_variant	1/25	5		ENSP00000422424.1	E9PE72

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000432

AC:

AN:

694028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

322080

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000473

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Type 2 diabetes mellitus;C2750078:Hypophosphatemic rickets, autosomal recessive, 2;C3809781:Hypopigmentation-punctate palmoplantar keratoderma syndrome;C4054476:Inherited obesity;C4551985:Arterial calcification, generalized, of infancy, 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.90

.;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

-0.19

PROVEAN

Benign

-0.47

N;.

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.93

P;P

Vest4

0.64

MutPred

0.99

Gain of MoRF binding (P = 0.0224);Gain of MoRF binding (P = 0.0224);

MVP

0.89

ClinPred

0.61

GERP RS

4.5

Varity_R

0.95

gMVP

0.28

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over