rs104894025
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001002010.5(NT5C3A):c.395A>T(p.Asp132Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,612,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
NT5C3A
NM_001002010.5 missense
NM_001002010.5 missense
Scores
9
3
1
Clinical Significance
Conservation
PhyloP100: 6.25
Genes affected
NT5C3A (HGNC:17820): (5'-nucleotidase, cytosolic IIIA) This gene encodes a member of the 5'-nucleotidase family of enzymes that catalyze the dephosphorylation of nucleoside 5'-monophosphates. The encoded protein is the type 1 isozyme of pyrimidine 5' nucleotidase and catalyzes the dephosphorylation of pyrimidine 5' monophosphates. Mutations in this gene are a cause of hemolytic anemia due to uridine 5-prime monophosphate hydrolase deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and pseudogenes of this gene are located on the long arm of chromosomes 3 and 4. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
?
Variant 7-33021317-T-A is Pathogenic according to our data. Variant chr7-33021317-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NT5C3A | NM_001002010.5 | c.395A>T | p.Asp132Val | missense_variant | 5/9 | ENST00000610140.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NT5C3A | ENST00000610140.7 | c.395A>T | p.Asp132Val | missense_variant | 5/9 | 1 | NM_001002010.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250848Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135632
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1460054Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726404
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hemolytic anemia due to pyrimidine 5' nucleotidase deficiency Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 13, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 29, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NT5C3A protein function. ClinVar contains an entry for this variant (Variation ID: 4479). This missense change has been observed in individuals with pyrimidine 5'-nucleotidase deficiency (PMID: 11369620; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894025, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 98 of the NT5C3A protein (p.Asp98Val). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;D;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A
PrimateAI
Uncertain
T
REVEL
Pathogenic
Polyphen
1.0
.;.;D;D;D;.;D;.;.
Vest4
0.93, 0.94, 0.96, 0.93, 0.95
MutPred
0.85
.;.;.;Gain of sheet (P = 0.1208);.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at