rs121908249

Positions:

• chr6-131890435-A-C
• chr6-131890435-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006208.3(ENPP1):​c.2702A>C​(p.Tyr901Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000656 in 152,372 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 Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ENPP1 NM_006208.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.13

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 6-131890435-A-C is Pathogenic according to our data. Variant chr6-131890435-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 13596.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-131890435-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP1	NM_006208.3	c.2702A>C	p.Tyr901Ser	missense_variant	25/25	ENST00000647893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP1	ENST00000647893.1	c.2702A>C	p.Tyr901Ser	missense_variant	25/25		NM_006208.3	P1
ENPP1	ENST00000684674.1	n.1133A>C		non_coding_transcript_exon_variant	6/6
ENPP1	ENST00000513998.5	c.*1539A>C		3_prime_UTR_variant, NMD_transcript_variant	25/25	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 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: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152372 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74520

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 12, 2010	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.6	D;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.85		Gain of disorder (P = 0.0052);Gain of disorder (P = 0.0052);
MVP		0.91
MPC		0.93
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.87

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: rs121908249; hg19: chr6-132211575;