2-88691708-C-T

Variant names:

• chr2-88691708-C-T
• rs919043990
• NM_144563.3:c.10C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144563.3(RPIA):​c.10C>T​(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000351 in 1,426,212 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P4L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: RPIA NM_144563.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14
• Publications: 0 publications found

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]

EIF2AK3 (HGNC:3255): (eukaryotic translation initiation factor 2 alpha kinase 3) The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2, leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This protein is thought to modulate mitochondrial function. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins. Mutations in this gene are associated with Wolcott-Rallison syndrome. [provided by RefSeq, Sep 2015]

EIF2AK3 Gene-Disease associations (from GenCC):

• Wolcott-Rallison syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

LOC102724805 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144563.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPIA	NM_144563.3	MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 1 of 9	NP_653164.2	P49247

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPIA	ENST00000283646.5	TSL:1 MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 1 of 9	ENSP00000283646.3	P49247
	RPIA	ENST00000871060.1		c.10C>T	p.Pro4Ser	missense	Exon 1 of 9	ENSP00000541119.1
	RPIA	ENST00000871058.1		c.10C>T	p.Pro4Ser	missense	Exon 1 of 8	ENSP00000541117.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000485 AC: 1 AN: 206130 AF XY: 0.00

Gnomad AFR exome AF: 0.0000776

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1426212 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 708302

African (AFR) AF: 0.0000308 AC: 1 AN: 32454

American (AMR) AF: 0.00 AC: 0 AN: 41220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24260

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.00 AC: 0 AN: 82792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4028

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1101624

Other (OTH) AF: 0.00 AC: 0 AN: 58914

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.73	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.14		Gain of MoRF binding (P = 0.0182)
MVP		0.87
MPC		0.60
ClinPred		0.63	D
GERP RS		4.9
PromoterAI		0.0041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.24
gMVP		0.44
Mutation Taster		=91/9	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

Other links and lift over

dbSNP: rs919043990; hg19: chr2-88991226;