rs1044548

Variant names:

• chr6-131890623-G-A
• rs1044548
• NM_006208.3:c.*112G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006208.3(ENPP1):​c.*112G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 947,804 control chromosomes in the GnomAD database, including 3,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1949 hom., cov: 32)
  • Exomes 𝑓: 0.053 (1923 hom.)
• Consequence: ENPP1 NM_006208.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.01
• Publications: 9 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
• hypopigmentation-punctate palmoplantar keratoderma syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-131890623-G-A is Benign according to our data. Variant chr6-131890623-G-A is described in ClinVar as Benign. ClinVar VariationId is 355357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	NM_006208.3	MANE Select	c.*112G>A		3_prime_UTR	Exon 25 of 25	NP_006199.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	ENST00000647893.1	MANE Select	c.*112G>A		3_prime_UTR	Exon 25 of 25	ENSP00000498074.1
	ENPP1	ENST00000513998.5	TSL:5	n.*1727G>A		non_coding_transcript_exon	Exon 25 of 25	ENSP00000422424.1
	ENPP1	ENST00000684674.1		n.1321G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17663 AN: 152092 Hom.: 1931 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0815

Gnomad ASJ AF: 0.0423

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.120

GnomAD4 exome AF: 0.0527 AC: 41923 AN: 795594 Hom.: 1923 Cov.: 10 AF XY: 0.0516 AC XY: 21626 AN XY: 419290

African (AFR) AF: 0.296 AC: 5835 AN: 19692

American (AMR) AF: 0.0536 AC: 2119 AN: 39548

Ashkenazi Jewish (ASJ) AF: 0.0442 AC: 955 AN: 21602

East Asian (EAS) AF: 0.000144 AC: 5 AN: 34834

South Asian (SAS) AF: 0.0445 AC: 3095 AN: 69522

European-Finnish (FIN) AF: 0.0196 AC: 865 AN: 44170

Middle Eastern (MID) AF: 0.0936 AC: 289 AN: 3086

European-Non Finnish (NFE) AF: 0.0498 AC: 26123 AN: 524998

Other (OTH) AF: 0.0691 AC: 2637 AN: 38142

GnomAD4 genome AF: 0.116 AC: 17718 AN: 152210 Hom.: 1949 Cov.: 32 AF XY: 0.114 AC XY: 8476 AN XY: 74430

African (AFR) AF: 0.295 AC: 12222 AN: 41462

American (AMR) AF: 0.0814 AC: 1246 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 147 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0408 AC: 197 AN: 4824

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10618

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.0501 AC: 3405 AN: 68020

Other (OTH) AF: 0.119 AC: 251 AN: 2116

Alfa AF: 0.0695 Hom.: 1103

Bravo AF: 0.130

Asia WGS AF: 0.0370 AC: 130 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.83
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1044548; hg19: chr6-132211763;