chrX-154534125-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM1PM5PP2PP3_ModeratePP5BS2_Supporting

The NM_001360016.2(G6PD):c.680G>A(p.Arg227Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000636 in 1,210,410 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000063 ( 0 hom. 24 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2O:1

Conservation

PhyloP100: 5.50

Publications

58 publications found

Variant links:

Genes affected

G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

G6PD Gene-Disease associations (from GenCC):

anemia, nonspherocytic hemolytic, due to G6PD deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
G6PD deficiency
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
class I glucose-6-phosphate dehydrogenase deficiency
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

G6PD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001360016.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154534125-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10387.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 185 curated pathogenic missense variants (we use a threshold of 10). The gene has 42 curated benign missense variants. Gene score misZ: 2.0008 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

PP5

Variant X-154534125-C-T is Pathogenic according to our data. Variant chrX-154534125-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10395.

BS2

High Hemizygotes in GnomAd4 at 6 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2 link	c.680G>A	p.Arg227Gln	missense_variant	Exon 7 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 link	c.770G>A	p.Arg257Gln	missense_variant	Exon 7 of 13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 link	c.680G>A	p.Arg227Gln	missense_variant	Exon 7 of 13		NP_001035810.1	P11413-1A0A384NL00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10 link	c.680G>A	p.Arg227Gln	missense_variant	Exon 7 of 13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.0000713

AC:

AN:

112270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000750

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000491

AC:

AN:

183199

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000628

AC:

AN:

1098140

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

363506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.000170

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40502

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.0000653

AC:

AN:

842095

Other (OTH)

AF:

0.000152

AC:

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000713

AC:

AN:

112270

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

34432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30904

American (AMR)

AF:

0.000750

AC:

AN:

10672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3562

South Asian (SAS)

AF:

0.00

AC:

AN:

2717

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53132

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000235

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:3Uncertain:1

Aug 12, 2022

Dunham Lab, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Variant found in hemizygote with deficiency (PP4). Decreased activity in red blood cells (35%) (PS3). Affects same amino acid as pathogenic 227R>L (ClinVar ID 10387) (PM5). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by ARUP Laboratories (PP5). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -

Jun 14, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the G6PD protein (p.Arg227Gln). This variant is present in population databases (rs137852328, gnomAD 0.02%). This missense change has been observed in individual(s) with G6PD deficiency (PMID: 1611091). This variant is also known as G6PD Mexico City. ClinVar contains an entry for this variant (Variation ID: 10395). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function. Experimental studies have shown that this missense change affects G6PD function (PMID: 25407525). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg227 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been observed in individuals with G6PD-related conditions (PMID: 10571945), which suggests that this may be a clinically significant amino acid residue. 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. -

not specified

Pathogenic:1

Sep 21, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

G6PD deficiency

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

G6PD MEXICO CITY

Other:1

May 24, 2017

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D;D;.;D;.;D

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;.;D;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;M;M;M;.;.;.

PhyloP100

5.5

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.7

.;.;D;D;D;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0050

.;.;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;.;D;D;.;.;.

Polyphen

0.94

P;P;P;.;.;.;.

Vest4

0.75

MVP

1.0

MPC

1.3

ClinPred

0.43

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.98

Mutation Taster

=45/55

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over