rs750410843

Variant names:

• chr6-131808026-C-T
• rs750410843
• NM_006208.3:c.-10C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-131808026-C-T
• chr6-131808026-C-G

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.907
• Publications: 0 publications found

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]

ENPP1 Gene-Disease associations (from GenCC):

• arterial calcification, generalized, of infancy, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• hypopigmentation-punctate palmoplantar keratoderma syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hypophosphatemic rickets, autosomal recessive, 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hypophosphatemic rickets

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive inherited pseudoxanthoma elasticum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 193334.
• 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 the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	NM_006208.3	MANE Select	c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	NP_006199.2	P22413
	ENPP1	NM_006208.3	MANE Select	c.-10C>T		5_prime_UTR	Exon 1 of 25	NP_006199.2	P22413

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	ENST00000647893.1	MANE Select	c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	ENSP00000498074.1	P22413
	ENPP1	ENST00000647893.1	MANE Select	c.-10C>T		5_prime_UTR	Exon 1 of 25	ENSP00000498074.1	P22413
	ENPP1	ENST00000922186.1		c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000592245.1

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

GnomAD2 exomes AF: 0.500 AC: 1 AN: 2

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

African (AFR) AF: 0.00526 AC: 54 AN: 10270

American (AMR) AF: 0.0295 AC: 20 AN: 678

Ashkenazi Jewish (ASJ) AF: 0.00985 AC: 32 AN: 3248

East Asian (EAS) AF: 0.00 AC: 0 AN: 2418

South Asian (SAS) AF: 0.0224 AC: 234 AN: 10454

European-Finnish (FIN) AF: 0.0462 AC: 11 AN: 238

Middle Eastern (MID) AF: 0.0450 AC: 46 AN: 1022

European-Non Finnish (NFE) AF: 0.0393 AC: 19080 AN: 485108

Other (OTH) AF: 0.0356 AC: 617 AN: 17310

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

African (AFR) AF: 0.00624 AC: 158 AN: 25338

American (AMR) AF: 0.0516 AC: 338 AN: 6548

Ashkenazi Jewish (ASJ) AF: 0.00613 AC: 17 AN: 2772

East Asian (EAS) AF: 0.000704 AC: 2 AN: 2840

South Asian (SAS) AF: 0.0277 AC: 75 AN: 2706

European-Finnish (FIN) AF: 0.0793 AC: 149 AN: 1880

Middle Eastern (MID) AF: 0.106 AC: 14 AN: 132

European-Non Finnish (NFE) AF: 0.0312 AC: 1600 AN: 51246

Other (OTH) AF: 0.0306 AC: 40 AN: 1306

Alfa AF: 0.0224 Hom.: 8

Bravo AF: 0.0159

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Arterial calcification, generalized, of infancy, 1 (1)
-	-	1	Hypophosphatemic rickets, autosomal recessive, 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.4
DANN	Benign	0.89
PhyloP100		-0.91
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs750410843; hg19: chr6-132129166;