rs76645461

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_001360016.2(G6PD):c.143T>C(p.Ile48Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,209,926 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. 5 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 7.09

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001360016.2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

PP5

Variant X-154536156-A-G is Pathogenic according to our data. Variant chrX-154536156-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154536156-A-G is described in Lovd as [Pathogenic]. Variant chrX-154536156-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
G6PD	NM_001360016.2 linkuse as main transcript	c.143T>C	p.Ile48Thr	missense_variant	3/13	ENST00000393562.10
G6PD	NM_000402.4 linkuse as main transcript	c.233T>C	p.Ile78Thr	missense_variant	3/13
G6PD	NM_001042351.3 linkuse as main transcript	c.143T>C	p.Ile48Thr	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10 linkuse as main transcript	c.143T>C	p.Ile48Thr	missense_variant	3/13	1	NM_001360016.2	P4	P11413-1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111765

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33947

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:

0.000281

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

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183351

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67819

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad SAS 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:

0.0000146

AC:

AN:

1098104

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363460

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34014

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000282

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jan 29, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with anemia and jaundice (PP4, PS4_M). Decreased activity in red blood cells (3-35%) (PS3). In silico analysis supports that this missense variant has a deleterious effect (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.997 (odds of pathogenicity 3155, Prior_P 0.1). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 48 of the G6PD protein (p.Ile48Thr). This variant is present in population databases (rs76645461, gnomAD 0.02%). This missense change has been observed in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (PMID: 8490627, 16119988, 22018328, 22963789). This variant is also known as the Aures variant. ClinVar contains an entry for this variant (Variation ID: 10402). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on G6PD protein function. Experimental studies have shown that this missense change affects G6PD function (PMID: 8490627, 22963789). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 27, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20236109, 8787363, 27853304, 12972027, 8860007, 16119988, 22963789, 22018328, 23006493, 21931771, 27884173, 8490627, 34272389, 31589614, 28902532) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 01, 2021	The G6PD c.143T>C; p.Ile48Thr variant (rs76645461), also known as G6PD Aures, is reported in the literature in multiple individuals affected with G6PD deficiency (Alfadhli 2005, Al-Jaouni 2011, Benmansour 2013, Nafa 1993). Individuals with this variant have reduced G6PD enzyme activity and is classified as a WHO Class III variant (Benmansour 2013). This variant is also reported in ClinVar (Variation ID: 10402) and is found in the East Asian population with an allele frequency of 0.01% (2/13861 alleles) in the Genome Aggregation Database. The isoleucine at codon 48 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.8). Based on available information, this variant is considered to be pathogenic. References: Alfadhli S et al. Molecular characterization of glucose-6-phosphate dehydrogenase gene defect in the Kuwaiti population. Arch Pathol Lab Med. 2005 Sep;129(9):1144-7. PMID: 16119988. Al-Jaouni SK et al. Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Jeddah, Kingdom of Saudi Arabia. BMC Res Notes. 2011 Oct 24;4:436. PMID: 22018328. Benmansour I et al. Two new class III G6PD variants [G6PD Tunis (c.920A>C: p.307Gln>Pro) and G6PD Nefza (c.968T>C: p.323 Leu>Pro)] and overview of the spectrum of mutations in Tunisia. Blood Cells Mol Dis. 2013 Feb;50(2):110-4. PMID: 22963789. Nafa K et al. G6PD Aures: a new mutation (48 Ile-->Thr) causing mild G6PD deficiency is associated with favism. Hum Mol Genet. 1993 Jan;2(1):81-2. PMID: 8490627. -

Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 11, 2021

- -

Malaria, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 26, 2023

- -

G6PD deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 16, 2021

The G6PD c.233T>C (p.Ile78Thr) variant is a missense variant. Across a selection of the available literature, this variant, which is also known as the G6PD Aures variant, has been reported in 92 individuals with glucose-6-phosphate dehydrogenase deficiency, including in a hemizygous state in 66 males, in a homozygous state in 15 females, and in 11 cases of unspecified sex/zygosity (Nafa et al. 1993; AlFadhli et al. 2005; Al-Jaouni et al. 2011; Dallol et al. 2012; Benmansour et al. 2013; Sanephonasa et al. 2021). The p.Ile78Thr variant is reported at a frequency of 0.000144 in the East Asian population of the Genome Aggregation Database (version 2.1.1), but this frequency is based on only two alleles in a region of good sequencing coverage. Multiple in silico algorithms consistently predict a functional consequence of this variant, and carriers of this variant have been confirmed to have reduced G6PD enzyme activity (Dallol et al. 2012). Based on the available evidence, the p.Ile78Thr variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. -

G6PD AURES

Other:1

other, no assertion criteria provided

literature only

OMIM

Apr 18, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.63

Cadd

Uncertain

Dann

Benign

0.88

DEOGEN2

Pathogenic

0.86

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

FATHMM_MKL

Uncertain

0.96

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.92

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

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

1.4

L;L;L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.81

Sift4G

Benign

0.77

T;.;T;T;.;.;.

Polyphen

0.98

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

Vest4

0.80

MutPred

0.96

Gain of disorder (P = 0.0198);Gain of disorder (P = 0.0198);Gain of disorder (P = 0.0198);Gain of disorder (P = 0.0198);Gain of disorder (P = 0.0198);Gain of disorder (P = 0.0198);Gain of disorder (P = 0.0198);

MVP

1.0

MPC

0.80

ClinPred

0.35

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.98

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over