6-46161705-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001290072.2(ENPP5):​c.1055T>A​(p.Phe352Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ENPP5
NM_001290072.2 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.40
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ENPP5NM_001290072.2 linkuse as main transcriptc.1055T>A p.Phe352Tyr missense_variant 5/5 ENST00000371383.7 NP_001277001.1 Q9UJA9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ENPP5ENST00000371383.7 linkuse as main transcriptc.1055T>A p.Phe352Tyr missense_variant 5/51 NM_001290072.2 ENSP00000360436.1 Q9UJA9
ENPP5ENST00000230565.3 linkuse as main transcriptc.1055T>A p.Phe352Tyr missense_variant 4/41 ENSP00000230565.3 Q9UJA9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250536
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135466
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461040
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
726834
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 04, 2024The c.1055T>A (p.F352Y) alteration is located in exon 4 (coding exon 3) of the ENPP5 gene. This alteration results from a T to A substitution at nucleotide position 1055, causing the phenylalanine (F) at amino acid position 352 to be replaced by a tyrosine (Y). 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
Pathogenic
0.68
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T;T
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
.;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.36
D
MutationAssessor
Pathogenic
3.0
M;M
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.3
N;N
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
1.0
D;D
Vest4
0.61
MutPred
0.88
Gain of catalytic residue at I351 (P = 0.0352);Gain of catalytic residue at I351 (P = 0.0352);
MVP
0.66
MPC
0.66
ClinPred
0.90
D
GERP RS
5.6
Varity_R
0.88
gMVP
0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1295541658; hg19: chr6-46129442; API