X-75274469-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_145052.4(UPRT):​c.215C>T​(p.Ser72Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,209,768 control chromosomes in the GnomAD database, including 1 homozygotes. There are 269 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., 13 hem., cov: 23)
Exomes 𝑓: 0.00066 ( 1 hom. 256 hem. )

Consequence

UPRT
NM_145052.4 missense

Scores

2
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.0900
Variant links:
Genes affected
UPRT (HGNC:28334): (uracil phosphoribosyltransferase homolog) This gene encodes uracil phosphoribosyltransferase, which catalyzes the conversion of uracil and 5-phosphoribosyl-1-R-diphosphate to uridine monophosphate (UMP). This reaction is an important part of nucleotide metabolism, specifically the pyrimidine salvage pathway. The enzyme localizes to the nucleus and cytoplasm. The protein is a potential target for rational design of drugs to treat parasitic infections and cancer. [provided by RefSeq, Nov 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0054303706).
BP6
Variant X-75274469-C-T is Benign according to our data. Variant chrX-75274469-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1206381.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chrX-75274469-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000665 (730/1097877) while in subpopulation MID AF= 0.0215 (89/4132). AF 95% confidence interval is 0.0179. There are 1 homozygotes in gnomad4_exome. There are 256 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 13 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
UPRTNM_145052.4 linkc.215C>T p.Ser72Phe missense_variant Exon 1 of 7 ENST00000373383.9 NP_659489.1 Q96BW1-1A8KAF9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UPRTENST00000373383.9 linkc.215C>T p.Ser72Phe missense_variant Exon 1 of 7 1 NM_145052.4 ENSP00000362481.4 Q96BW1-1

Frequencies

GnomAD3 genomes
AF:
0.000438
AC:
49
AN:
111840
Hom.:
1
Cov.:
23
AF XY:
0.000382
AC XY:
13
AN XY:
34000
show subpopulations
Gnomad AFR
AF:
0.0000976
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000284
Gnomad ASJ
AF:
0.00302
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0210
Gnomad NFE
AF:
0.000489
Gnomad OTH
AF:
0.00266
GnomAD3 exomes
AF:
0.000691
AC:
125
AN:
180895
Hom.:
0
AF XY:
0.000727
AC XY:
48
AN XY:
66047
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000697
Gnomad ASJ exome
AF:
0.00457
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000159
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000745
Gnomad OTH exome
AF:
0.00203
GnomAD4 exome
AF:
0.000665
AC:
730
AN:
1097877
Hom.:
1
Cov.:
30
AF XY:
0.000705
AC XY:
256
AN XY:
363283
show subpopulations
Gnomad4 AFR exome
AF:
0.000492
Gnomad4 AMR exome
AF:
0.000654
Gnomad4 ASJ exome
AF:
0.00547
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000240
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000475
Gnomad4 OTH exome
AF:
0.00187
GnomAD4 genome
AF:
0.000420
AC:
47
AN:
111891
Hom.:
0
Cov.:
23
AF XY:
0.000382
AC XY:
13
AN XY:
34061
show subpopulations
Gnomad4 AFR
AF:
0.0000973
Gnomad4 AMR
AF:
0.000283
Gnomad4 ASJ
AF:
0.00302
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000489
Gnomad4 OTH
AF:
0.00263
Alfa
AF:
0.000968
Hom.:
45
Bravo
AF:
0.000552
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000892
AC:
6
ExAC
AF:
0.000519
AC:
63

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Uncertain:1
Aug 08, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.215C>T (p.S72F) alteration is located in exon 1 (coding exon 1) of the UPRT gene. This alteration results from a C to T substitution at nucleotide position 215, causing the serine (S) at amino acid position 72 to be replaced by a phenylalanine (F). 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
0.085
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
13
DANN
Benign
0.97
DEOGEN2
Benign
0.18
T;.
FATHMM_MKL
Benign
0.021
N
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.0087
T
MetaRNN
Benign
0.0054
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N;.
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.067
Sift
Uncertain
0.010
D;D
Sift4G
Uncertain
0.035
D;D
Polyphen
0.019
B;.
Vest4
0.16
MVP
0.043
MPC
0.19
ClinPred
0.024
T
GERP RS
-2.2
Varity_R
0.061
gMVP
0.23

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: rs144630001; hg19: chrX-74494304; COSMIC: COSV99055594; COSMIC: COSV99055594; API