6-131808048-G-C

Variant names:

• chr6-131808048-G-C
• NM_006208.3:c.13G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006208.3(ENPP1):​c.13G>C​(p.Gly5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ENPP1 NM_006208.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29638168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.13G>C	p.Gly5Arg	missense_variant	Exon 1 of 25	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.13G>C	p.Gly5Arg	missense_variant	Exon 1 of 25		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.33G>C		non_coding_transcript_exon_variant	Exon 1 of 4	2
ENPP1	ENST00000513998.5	n.13G>C		non_coding_transcript_exon_variant	Exon 1 of 25	5		ENSP00000422424.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13G>C (p.G5R) alteration is located in exon 1 (coding exon 1) of the ENPP1 gene. This alteration results from a G to C substitution at nucleotide position 13, causing the glycine (G) at amino acid position 5 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.0065
Eigen_PC	Benign	-0.050
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.61	.;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.22	N;.
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.015	D;.
Polyphen		0.95	P;P
Vest4		0.28
MutPred		0.39		Gain of MoRF binding (P = 0.0039);Gain of MoRF binding (P = 0.0039);
MVP		0.81
MPC		0.24
ClinPred		0.60	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.12
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-132129188;