rs137852318

chrX-154533596-C-AchrX-154533596-C-GchrX-154533596-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001360016.2(G6PD):c.844G>T(p.Asp282Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D282H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.62

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 12 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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-154533596-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10372.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=17, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant X-154533596-C-A is Pathogenic according to our data. Variant chrX-154533596-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1722591.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154533596-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.844G>T	p.Asp282Tyr	missense_variant	8/13	ENST00000393562.10
G6PD	NM_000402.4	c.934G>T	p.Asp312Tyr	missense_variant	8/13
G6PD	NM_001042351.3	c.844G>T	p.Asp282Tyr	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.844G>T	p.Asp282Tyr	missense_variant	8/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

curation

Dunham Lab, University of Washington

Aug 12, 2022

Variant found in hemizygote with G6PD deficiency (PP4). Heterozygous mother and sister also have deficiency (PP1). Decreased activity in red blood cells (PS3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.975 (odds of pathogenicity 350.3, Prior_P 0.1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;D;.;D;.
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.9	H;H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.0020	D;.;D;D;.;.
Polyphen		1.0	D;D;D;.;.;.
Vest4		0.85
MutPred		0.84		Gain of phosphorylation at D282 (P = 0.0274);Gain of phosphorylation at D282 (P = 0.0274);Gain of phosphorylation at D282 (P = 0.0274);.;.;.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.99

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: rs137852318; hg19: chrX-153761811;