rs76645461

Variant names:

• chrX-154536156-A-G
• rs76645461
• NM_001360016.2:c.143T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PP2 PP3_Moderate PP5_Very_Strong BS2_Supporting

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 7.09
• Publications: 36 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 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
• 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, 0.925
• PP5: Variant X-154536156-A-G is Pathogenic according to our data. Variant chrX-154536156-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 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	c.143T>C	p.Ile48Thr	missense_variant	Exon 3 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.233T>C	p.Ile78Thr	missense_variant	Exon 3 of 13		NP_000393.4
G6PD	NM_001042351.3	c.143T>C	p.Ile48Thr	missense_variant	Exon 3 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.143T>C	p.Ile48Thr	missense_variant	Exon 3 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111765 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183351 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1098104 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363460

African (AFR) AF: 0.0000379 AC: 1 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00242 AC: 10 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842009

Other (OTH) AF: 0.0000868 AC: 4 AN: 46088

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111822 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34014

African (AFR) AF: 0.00 AC: 0 AN: 30821

American (AMR) AF: 0.00 AC: 0 AN: 10609

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.000282 AC: 1 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2653

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6105

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53012

Other (OTH) AF: 0.00 AC: 0 AN: 1535

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:7

May 17, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence 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 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. -

Jan 29, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 12, 2022

Dunham Lab, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

not provided Pathogenic:4

Jul 26, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PM2_moderate, PS4_moderate -

Jan 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G6PD c.143T>C; p.Ile48Thr variant (rs76645461; ClinVar Variation ID: 10402), 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 only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. 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. -

Apr 16, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 8787363, 12972027, 8860007, 16119988, 22963789, 21931771, 27884173, 8490627, 34272389, 31589614, 37644014, 37967096, 36681081, 36212142, 28902532, 23006493, 22018328, 27853304, 20236109) -

G6PD deficiency Pathogenic:2

May 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: G6PD c.233T>C (p.Ile78Thr) results in a non-conservative amino acid change located in the glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183351 control chromosomes. c.233T>C has been reported in the literature in the homozygous and hemizygous states in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Nafa_1993, Dallol_2012, Al-Jaouni_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant results in 7% G6PD activity compared to WT in patient red blood cells (e.g. Nafa_1993). This variant is also known as c.143T>C(p.Ile48Thr) and G6PD Aures. The following publications have been ascertained in the context of this evaluation (PMID: 22018328, 23006493, 8490627). ClinVar contains an entry for this variant (Variation ID: 10402). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 16, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1

Jun 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malaria, susceptibility to Pathogenic:1

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

G6PD-related disorder Pathogenic:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The G6PD c.143T>C variant is predicted to result in the amino acid substitution p.Ile48Thr. This variant, also referred to as G6PD Aures, has been reported in multiple individuals with glucose-6-phosphate dehydrogenase deficiency (Nafa et al. 1993. PubMed ID: 8490627; Doss et al. 2016. PubMed ID: 27853304). One male patient carrying this variant was reported to have G6PD activity of ~7% compared to wild type in whole blood (Nafa et al. 1993. PubMed ID: 8490627) and another report referred to the p.Ile48Thr as a mild allele (Doss et al. 2016. PubMed ID: 27853304). This variant is reported in 0.014% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

G6PD AURES Other:1

Apr 18, 2013

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	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.63
CADD	Uncertain	25
DANN	Benign	0.88
DEOGEN2	Pathogenic	0.86	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.4	L;L;L;L;.;.;.
PhyloP100		7.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.4	.;.;D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Benign	1.0	.;.;T;T;T;T;T
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	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs76645461; hg19: chrX-153764371;