2-88691703-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_144563.3(RPIA):c.5A>G(p.Gln2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,570,802 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

RPIA
NM_144563.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.72

Publications

3 publications found

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]

RPIA links:

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)

EIF2AK3 links:

LOC102724805 (HGNC:):

LOC102724805 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10805157).

BP6

Variant 2-88691703-A-G is Benign according to our data. Variant chr2-88691703-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 897554.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000046 (7/152294) while in subpopulation EAS AF = 0.00135 (7/5180). AF 95% confidence interval is 0.000634. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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.5A>G	p.Gln2Arg	missense	Exon 1 of 9	NP_653164.2	P49247

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPIA	ENST00000283646.5	TSL:1 MANE Select	c.5A>G	p.Gln2Arg	missense	Exon 1 of 9	ENSP00000283646.3	P49247
RPIA	ENST00000871060.1		c.5A>G	p.Gln2Arg	missense	Exon 1 of 9	ENSP00000541119.1
RPIA	ENST00000871058.1		c.5A>G	p.Gln2Arg	missense	Exon 1 of 8	ENSP00000541117.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

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

GnomAD2 exomes

AF:

0.0000914

AC:

AN:

196906

AF XY:

0.0000818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000184

AC:

261

AN:

1418508

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

124

AN XY:

704214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32008

American (AMR)

AF:

0.00

AC:

AN:

39496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23708

East Asian (EAS)

AF:

0.00638

AC:

250

AN:

39192

South Asian (SAS)

AF:

0.00

AC:

AN:

81458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3990

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1099050

Other (OTH)

AF:

0.000136

AC:

AN:

58616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41556

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000941

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of ribose-5-phosphate isomerase (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.9

PhyloP100

1.7

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.57

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.55

MutPred

0.21

Gain of MoRF binding (P = 0.0037)

MVP

0.82

MPC

1.2

ClinPred

0.27

GERP RS

4.8

PromoterAI

0.090

Neutral

(source)

Varity_R

0.52

gMVP

0.45

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over