6-131860388-G-T

Position:

• chr6-131860388-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_006208.3(ENPP1):​c.797G>T​(p.Gly266Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,593,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G266R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ENPP1 NM_006208.3 missense, splice_region
• Scores: Splicing: ADA: 0.9693
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 9.27

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-131860387-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 6-131860388-G-T is Pathogenic according to our data. Variant chr6-131860388-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13594.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-131860388-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.797G>T	p.Gly266Val	missense_variant, splice_region_variant	8/25	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.797G>T	p.Gly266Val	missense_variant, splice_region_variant	8/25		NM_006208.3	ENSP00000498074.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151846 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1441694 Hom.: 0 Cov.: 27 AF XY: 0.00000417 AC XY: 3 AN XY: 718566

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: 0.00000365

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151846 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74154

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypophosphatemic rickets, autosomal recessive, 2 Pathogenic:2 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 12, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 05, 2013	- -

Arterial calcification, generalized, of infancy, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 12, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.7	D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.96		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.99
MPC		0.89
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.81
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: rs121908248; hg19: chr6-132181528;