6-46161493-C-T

Position:

• chr6-46161493-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001290072.2(ENPP5):​c.1267G>A​(p.Ala423Thr) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ENPP5 NM_001290072.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.158

Genes affected

ENPP5 (HGNC:13717): (ectonucleotide pyrophosphatase/phosphodiesterase family member 5) This gene encodes a type-I transmembrane glycoprotein. Studies in rat suggest the encoded protein may play a role in neuronal cell communications. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03888771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP5	NM_001290072.2	c.1267G>A	p.Ala423Thr	missense_variant	5/5	ENST00000371383.7	NP_001277001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP5	ENST00000371383.7	c.1267G>A	p.Ala423Thr	missense_variant	5/5	1	NM_001290072.2	ENSP00000360436.1
ENPP5	ENST00000230565.3	c.1267G>A	p.Ala423Thr	missense_variant	4/4	1		ENSP00000230565.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

The c.1267G>A (p.A423T) alteration is located in exon 4 (coding exon 3) of the ENPP5 gene. This alteration results from a G to A substitution at nucleotide position 1267, causing the alanine (A) at amino acid position 423 to be replaced by a threonine (T). 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	0.063
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.4
DANN	Benign	0.47
DEOGEN2	Benign	0.0010	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.58	.;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.11
Sift	Benign	0.45	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.012	B;B
Vest4		0.047
MutPred		0.15		Gain of glycosylation at A423 (P = 0.0242);Gain of glycosylation at A423 (P = 0.0242);
MVP		0.099
MPC		0.13
ClinPred		0.030	T
GERP RS		-1.4
Varity_R		0.029
gMVP		0.29

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: chr6-46129230;