Menu
GeneBe

2-88691709-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_144563.3(RPIA):c.11C>T(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000735 in 1,578,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

RPIA
NM_144563.3 missense

Scores

1
10
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.22
Variant links:
Genes affected
RPIA (HGNC:10297): (ribose 5-phosphate isomerase A) The protein encoded by this gene is an enzyme, which catalyzes the reversible conversion between ribose-5-phosphate and ribulose-5-phosphate in the pentose-phosphate pathway. This gene is highly conserved in most organisms. The enzyme plays an essential role in the carbohydrate metabolism. Mutations in this gene cause ribose 5-phosphate isomerase deficiency. A pseudogene is found on chromosome 18. [provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06857458).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000427 (65/152354) while in subpopulation AFR AF= 0.00149 (62/41582). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPIANM_144563.3 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/9 ENST00000283646.5
RPIAXM_047443733.1 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPIAENST00000283646.5 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/91 NM_144563.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000427
AC:
65
AN:
152236
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00150
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000922
AC:
19
AN:
206124
Hom.:
0
AF XY:
0.0000958
AC XY:
11
AN XY:
114836
show subpopulations
Gnomad AFR exome
AF:
0.00140
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:
0.0000107
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000358
AC:
51
AN:
1426300
Hom.:
0
Cov.:
32
AF XY:
0.0000325
AC XY:
23
AN XY:
708342
show subpopulations
Gnomad4 AFR exome
AF:
0.00142
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000240
Gnomad4 NFE exome
AF:
9.08e-7
Gnomad4 OTH exome
AF:
0.0000509
GnomAD4 genome
AF:
0.000427
AC:
65
AN:
152354
Hom.:
0
Cov.:
33
AF XY:
0.000429
AC XY:
32
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.00149
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000525
ESP6500AA
AF:
0.000314
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000137
AC:
16
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 03, 2022This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the RPIA protein (p.Pro4Leu). This variant is present in population databases (rs199519092, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with RPIA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
T
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.72
T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.069
T
MetaSVM
Uncertain
-0.28
T
MutationAssessor
Uncertain
2.0
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.3
N
REVEL
Uncertain
0.31
Sift
Benign
0.071
T
Sift4G
Uncertain
0.0070
D
Polyphen
1.0
D
Vest4
0.58
MVP
0.90
MPC
0.37
ClinPred
0.13
T
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.21
gMVP
0.44

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: rs199519092; hg19: chr2-88991227; API