rs115371819

chr6-131879936-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006208.3(ENPP1):c.2002G>A(p.Glu668Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,613,632 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (41 hom.)
• Consequence: ENPP1 NM_006208.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 1.77

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022817552).
• BP6: Variant 6-131879936-G-A is Benign according to our data. Variant chr6-131879936-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 161094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-131879936-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (2108/152186) while in subpopulation AFR AF= 0.0485 (2015/41518). AF 95% confidence interval is 0.0468. There are 53 homozygotes in gnomad4. There are 993 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP1	NM_006208.3	c.2002G>A	p.Glu668Lys	missense_variant	20/25	ENST00000647893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP1	ENST00000647893.1	c.2002G>A	p.Glu668Lys	missense_variant	20/25		NM_006208.3	P1
ENPP1	ENST00000647981.1	n.732G>A		non_coding_transcript_exon_variant	9/10
ENPP1	ENST00000684674.1	n.433G>A		non_coding_transcript_exon_variant	1/6
ENPP1	ENST00000513998.5	c.*839G>A		3_prime_UTR_variant, NMD_transcript_variant	20/25	5

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2102 AN: 152068 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00407

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: 0.000176

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00344 AC: 865 AN: 251352 Hom.: 13 AF XY: 0.00254 AC XY: 345 AN XY: 135820

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00143 AC: 2094 AN: 1461446 Hom.: 41 Cov.: 30 AF XY: 0.00125 AC XY: 906 AN XY: 727070

Gnomad4 AFR exome AF: 0.0510

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.0139 AC: 2108 AN: 152186 Hom.: 53 Cov.: 32 AF XY: 0.0133 AC XY: 993 AN XY: 74424

Gnomad4 AFR AF: 0.0485

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00241 Hom.: 13

Bravo AF: 0.0149

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00432 AC: 525

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2019	This variant is associated with the following publications: (PMID: 27467858, 12881724, 21228398, 20981092) -

Arterial calcification, generalized, of infancy, 1 Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 28, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	3.3
Dann	Benign	0.40
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.022	N
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.77	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.15	N;.
REVEL	Benign	0.095
Sift	Benign	0.48	T;.
Sift4G	Benign	0.84	T;.
Polyphen		0.0	B;B
Vest4		0.12
MVP		0.54
MPC		0.23
ClinPred		0.0026	T
GERP RS		4.4
Varity_R		0.019
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115371819; hg19: chr6-132201076; COSMIC: COSV62934452; COSMIC: COSV62934452;