2-88691852-C-T

Variant names:

• chr2-88691852-C-T
• rs962744633
• NM_144563.3:c.154C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_144563.3(RPIA):​c.154C>T​(p.Arg52Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,595,650 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: RPIA NM_144563.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.117

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity RPIA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.110238016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPIA	NM_144563.3	c.154C>T	p.Arg52Cys	missense_variant	Exon 1 of 9	ENST00000283646.5	NP_653164.2
RPIA	XM_047443733.1	c.154C>T	p.Arg52Cys	missense_variant	Exon 1 of 6		XP_047299689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPIA	ENST00000283646.5	c.154C>T	p.Arg52Cys	missense_variant	Exon 1 of 9	1	NM_144563.3	ENSP00000283646.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151906 Hom.: 0 Cov.: 33

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: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000970 AC: 2 AN: 206270 AF XY: 0.00000884

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000229 AC: 33 AN: 1443744 Hom.: 1 Cov.: 32 AF XY: 0.0000279 AC XY: 20 AN XY: 716576

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33382

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 41390

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25602

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39096

Gnomad4 SAS exome AF: 0.0000359 AC: 3 AN: 83628

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 50550

Gnomad4 NFE exome AF: 0.0000272 AC: 30 AN: 1104682

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 59758

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151906 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74190

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.00020816 AN: 0.00020816

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000441 AC: 0.0000441462 AN: 0.0000441462

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 13, 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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 52 of the RPIA protein (p.Arg52Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RPIA-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.39		Loss of solvent accessibility (P = 1e-04);
MVP		0.60
MPC		0.49
ClinPred		0.28	T
GERP RS		-0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.46
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs962744633; hg19: chr2-88991370;