rs5030872

chrX-154534440-T-AchrX-154534440-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 10P and 5B. PM1 PP5_Very_Strong BP4 BS2

The NM_001360016.2(G6PD):c.542A>T(p.Asp181Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000777 in 1,209,769 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.000041 (0 hom. 15 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001360016.2
• PP5: Variant X-154534440-T-A is Pathogenic according to our data. Variant chrX-154534440-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534440-T-A is described in Lovd as [Pathogenic]. Variant chrX-154534440-T-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.16829187).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.542A>T	p.Asp181Val	missense_variant	6/13	ENST00000393562.10
G6PD	NM_000402.4	c.632A>T	p.Asp211Val	missense_variant	6/13
G6PD	NM_001042351.3	c.542A>T	p.Asp181Val	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.542A>T	p.Asp181Val	missense_variant	6/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.000438 AC: 49 AN: 111781 Hom.: 0 Cov.: 23 AF XY: 0.000206 AC XY: 7 AN XY: 33999

Gnomad AFR AF: 0.00124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00103

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

GnomAD3 exomes AF: 0.000136 AC: 25 AN: 183162 Hom.: 0 AF XY: 0.000103 AC XY: 7 AN XY: 67684

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000410 AC: 45 AN: 1097988 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 15 AN XY: 363384

Gnomad4 AFR exome AF: 0.000871

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.000438 AC: 49 AN: 111781 Hom.: 0 Cov.: 23 AF XY: 0.000206 AC XY: 7 AN XY: 33999

Gnomad4 AFR AF: 0.00124

Gnomad4 AMR AF: 0.00103

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000754 Hom.: 1

Bravo AF: 0.000536

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2023	Biochemical studies of G6PD enzyme activity from patient blood samples showed that G6PD Malaga (D181V) and G6PD Santamaria (D181V+N126D) have similar abnormal kinetic properties, though G6PD Santamaria showed additional abnormalities thought to be due to the interaction of both variants (Vuilliamy et al., 1996); Published functional studies demonstrate that the G6PD Santamaria variant (D181V+N126D) causes lower levels of expression of soluble protein as well as reduced enzyme activity compared to both wild-type GP6D and G6PD harboring the N126D variant alone (Gomez-Manzo et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27267757, 33637102, 21931771, 26633385, 26738565, 17611006, 10571945, 6433630, 1879833, 9233561, 8956035, 34272389, 31589614, 36007526) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 08, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	G6PD: PM2, PS4:Moderate, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 14, 2021	PS3, PS4 -

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 181 of the G6PD protein (p.Asp181Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. The c.542A>T (p.Asp181Val) variant and the c.376A>G (p.Asn126Asp) variant, when co-occurring in cis as c.[376A>G;542A>T], is known as the G6PD Santa Maria haplotype. The c.542A>T (p.Asn181Val) variant alone (PMID: 10571945, 8956035) and the Santa Maria haplotype (PMID: 1879833, 22963789, 12367584, 8956035, 22906837) have both been observed in individuals affected with G6PD deficiency. ClinVar contains an entry for this variant (Variation ID: 37203). 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 are not available for the c.542A>T (p.Asn181Val) variant alone, but in vitro studies have shown that the G6PD Santa Maria haplotype abrogates enzyme activity and reduces affinity for the substrate (PMID: 26633385). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, favism, and anemia (PS4_M, PP4). Decreased activity in red blood cells (6%) (PS3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -

Malaria, susceptibility to Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 20, 2023

- -

G6PD MALAGA Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Benign	20
Dann	Benign	0.91
DEOGEN2	Pathogenic	0.81	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	-0.29	N;N;N;N;.;.;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.16	T;.;T;T;.;.;.
Polyphen		0.0080	B;B;B;.;.;.;.
Vest4		0.68
MVP		1.0
MPC		0.29
ClinPred		0.057	T
GERP RS		5.7
Varity_R		0.71
gMVP		0.80

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

Other links and lift over

dbSNP: rs5030872; hg19: chrX-153762655;