6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_006208.3(ENPP1):​c.313+41_313+46dupGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 12 hom., cov: 0)
Exomes 𝑓: 0.0057 ( 2 hom. )

Consequence

ENPP1
NM_006208.3 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: -0.525
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1562/137248) while in subpopulation NFE AF= 0.0167 (1065/63794). AF 95% confidence interval is 0.0159. There are 12 homozygotes in gnomad4. There are 717 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ENPP1NM_006208.3 linkc.313+41_313+46dupGTGTGT intron_variant ENST00000647893.1 NP_006199.2 P22413

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ENPP1ENST00000647893.1 linkc.313+8_313+9insGTGTGT intron_variant NM_006208.3 ENSP00000498074.1 P22413
ENPP1ENST00000486853.1 linkn.333+8_333+9insGTGTGT intron_variant 2
ENPP1ENST00000513998.5 linkn.313+8_313+9insGTGTGT intron_variant 5 ENSP00000422424.1 E9PE72
ENPP1ENST00000650507.1 linkn.*149+8_*149+9insGTGTGT intron_variant ENSP00000497375.1 A0A3B3IST7

Frequencies

GnomAD3 genomes
AF:
0.0114
AC:
1560
AN:
137160
Hom.:
12
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.00402
Gnomad AMI
AF:
0.0986
Gnomad AMR
AF:
0.00808
Gnomad ASJ
AF:
0.00710
Gnomad EAS
AF:
0.00165
Gnomad SAS
AF:
0.0153
Gnomad FIN
AF:
0.00438
Gnomad MID
AF:
0.00360
Gnomad NFE
AF:
0.0167
Gnomad OTH
AF:
0.0125
GnomAD4 exome
AF:
0.00569
AC:
5938
AN:
1042824
Hom.:
2
Cov.:
14
AF XY:
0.00593
AC XY:
3132
AN XY:
528456
show subpopulations
Gnomad4 AFR exome
AF:
0.00153
Gnomad4 AMR exome
AF:
0.00547
Gnomad4 ASJ exome
AF:
0.00332
Gnomad4 EAS exome
AF:
0.000869
Gnomad4 SAS exome
AF:
0.00781
Gnomad4 FIN exome
AF:
0.00402
Gnomad4 NFE exome
AF:
0.00595
Gnomad4 OTH exome
AF:
0.00686
GnomAD4 genome
AF:
0.0114
AC:
1562
AN:
137248
Hom.:
12
Cov.:
0
AF XY:
0.0107
AC XY:
717
AN XY:
66762
show subpopulations
Gnomad4 AFR
AF:
0.00400
Gnomad4 AMR
AF:
0.00806
Gnomad4 ASJ
AF:
0.00710
Gnomad4 EAS
AF:
0.00165
Gnomad4 SAS
AF:
0.0153
Gnomad4 FIN
AF:
0.00438
Gnomad4 NFE
AF:
0.0167
Gnomad4 OTH
AF:
0.0135

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 17, 2024- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Arterial calcification, generalized, of infancy, 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingGenomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research CentreDec 18, 2024- -
Hypophosphatemic Rickets, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs59956343; hg19: chr6-132168996; API