6-131808026-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006208.3(ENPP1):c.-10C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.026 (41 hom., cov: 19)
  • Exomes 𝑓: 0.038 (247 hom.)
• Consequence: ENPP1 NM_006208.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.907

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-131808026-C-T is Benign according to our data. Variant chr6-131808026-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193334.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0256 (2441/95494) while in subpopulation AMR AF= 0.0516 (338/6548). AF 95% confidence interval is 0.0471. There are 41 homozygotes in gnomad4. There are 1147 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP1	NM_006208.3	c.-10C>T		5_prime_UTR_variant	1/25	ENST00000647893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP1	ENST00000647893.1	c.-10C>T		5_prime_UTR_variant	1/25		NM_006208.3	P1
ENPP1	ENST00000486853.1	n.11C>T		non_coding_transcript_exon_variant	1/4	2
ENPP1	ENST00000513998.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 2441 AN: 95458 Hom.: 41 Cov.: 19

Gnomad AFR AF: 0.00624

Gnomad AMI AF: 0.0661

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.00613

Gnomad EAS AF: 0.000704

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.0793

Gnomad MID AF: 0.109

Gnomad NFE AF: 0.0312

Gnomad OTH AF: 0.0308

GnomAD3 exomes AF: 0.500 AC: 1 AN: 2 Hom.: 0 AC XY: 0 AN XY: 0

Gnomad NFE exome AF: 0.500

GnomAD4 exome AF: 0.0379 AC: 20094 AN: 530746 Hom.: 247 Cov.: 3 AF XY: 0.0379 AC XY: 9325 AN XY: 246214

Gnomad4 AFR exome AF: 0.00526

Gnomad4 AMR exome AF: 0.0295

Gnomad4 ASJ exome AF: 0.00985

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0224

Gnomad4 FIN exome AF: 0.0462

Gnomad4 NFE exome AF: 0.0393

Gnomad4 OTH exome AF: 0.0356

GnomAD4 genome AF: 0.0256 AC: 2441 AN: 95494 Hom.: 41 Cov.: 19 AF XY: 0.0263 AC XY: 1147 AN XY: 43618

Gnomad4 AFR AF: 0.00624

Gnomad4 AMR AF: 0.0516

Gnomad4 ASJ AF: 0.00613

Gnomad4 EAS AF: 0.000704

Gnomad4 SAS AF: 0.0277

Gnomad4 FIN AF: 0.0793

Gnomad4 NFE AF: 0.0312

Gnomad4 OTH AF: 0.0306

Alfa AF: 0.0224 Hom.: 8

Bravo AF: 0.0159

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 08, 2018

- -

Hypophosphatemic rickets, autosomal recessive, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.4
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs750410843; hg19: chr6-132129166;