7-33014750-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001002010.5(NT5C3A):​c.976A>G​(p.Ile326Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

NT5C3A
NM_001002010.5 missense

Scores

5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.30131572).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NT5C3ANM_001002010.5 linkc.976A>G p.Ile326Val missense_variant Exon 9 of 9 ENST00000610140.7 NP_001002010.2 Q9H0P0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NT5C3AENST00000610140.7 linkc.976A>G p.Ile326Val missense_variant Exon 9 of 9 1 NM_001002010.5 ENSP00000476480.2 X6RM59

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152192
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
251000
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135702
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1460244
Hom.:
0
Cov.:
31
AF XY:
0.00000551
AC XY:
4
AN XY:
726446
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152310
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Apr 06, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with NT5C3A-related conditions. This variant is present in population databases (rs563703074, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 292 of the NT5C3A protein (p.Ile292Val). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.39
T;.;.;T;.;T;.;.
Eigen
Benign
0.048
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.78
.;T;T;T;.;T;.;.
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.30
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.32
T
MutationAssessor
Benign
1.6
.;.;.;L;.;.;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.85
.;N;N;.;.;.;N;N
REVEL
Uncertain
0.34
Sift
Benign
0.051
.;T;D;.;.;.;D;T
Sift4G
Benign
0.10
.;T;T;T;.;T;T;T
Polyphen
0.011, 0.056
.;.;B;B;B;.;B;.
Vest4
0.099, 0.25, 0.10, 0.25, 0.22
MutPred
0.73
.;.;.;Loss of catalytic residue at L336 (P = 0.0641);.;.;.;.;
MVP
0.78
MPC
0.20
ClinPred
0.30
T
GERP RS
5.9
Varity_R
0.31
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs563703074; hg19: chr7-33054362; COSMIC: COSV54240525; COSMIC: COSV54240525; API