rs1557229683

chrX-154532667-G-AchrX-154532667-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001360016.2(G6PD):c.1187C>T(p.Pro396Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging 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. P396A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532668-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1163784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-154532667-G-A is Pathogenic according to our data. Variant chrX-154532667-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 470161.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chrX-154532667-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.1187C>T	p.Pro396Leu	missense_variant	10/13	ENST00000393562.10
G6PD	NM_000402.4	c.1277C>T	p.Pro426Leu	missense_variant	10/13
G6PD	NM_001042351.3	c.1187C>T	p.Pro396Leu	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.1187C>T	p.Pro396Leu	missense_variant	10/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in hemizygote with deficiency and CNSHA (PP4). Decreased activity in red blood cells (1%) (PS3). Predicted to be damaging or deleterious by multiple computational algorithms (PP3). Within dimer interface (PM1). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2016	This sequence change replaces proline with leucine at codon 396 of the G6PD protein (p.Pro396Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 2 individuals affected with chronic hemolytic anemia with evidence of segregation in one of the families (PMID: 7959695, Invitae). In addition, a different missense substitution at this codon has been reported de novo in an individual affected with G6PD-deficiency (PMID:26275698). One experimental study has shown that heterozygous females had lower levels of mutant mRNA with this variant as compared to the wild-type mRNA in blood cells, which might indicate a preferential survival of cells where the X inactivation is acting on the mutated chromosome (PMID: 8808605). In summary, this variant is a rare missense change that has been reported in affected individuals and suggested to affect blood cell survival. Additional genetic and functional data are needed to further substantiate the pathogenicity this variant. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;.
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.7	H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	D
Sift4G	Pathogenic	0.0010	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.93
MutPred		0.97		Gain of catalytic residue at P396 (P = 0.072);Gain of catalytic residue at P396 (P = 0.072);Gain of catalytic residue at P396 (P = 0.072);.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1557229683; hg19: chrX-153760882;