rs72554665

Variant names:

• chrX-154532269-C-A
• rs72554665
• NM_001360016.2:c.1376G>T
• G6PD p.Arg459Leu

Your query was ambiguous. Multiple possible variants found:

• chrX-154532269-C-A
• chrX-154532269-C-G
• chrX-154532269-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS3PM5PP3PP5_Strong

The NM_001360016.2(G6PD):c.1376G>T (p.Arg459Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000133 (AC=161) in the gnomAD database across 1,209,798 control chromosomes, including 44 hemizygotes. The grpmax filtering allele frequency (95% CI) is 0.00557. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000768476: Experimental studies have shown that this missense change affects G6PD function (PMID:16607506)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R459C: Likely_pathogenic (ClinVar VariationId 1469858, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 12 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 32 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 O:4
• Conservation: PhyloP100: 3.69
• Publications: 197 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• G6PD deficiency

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• class I glucose-6-phosphate dehydrogenase deficiency

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000768476: Experimental studies have shown that this missense change affects G6PD function (PMID: 16607506).; SCV002599395: Decreased activity in red blood cells (1-52%) (PS3).; SCV005416896: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005908351: Previous experiments have shown that this missense variation will lead to enzyme activity and affinity for glucose 6- phosphate. Significantly decreased (PMID:16607506), the mutation of the same site leading to the change to another amino acid has been confirmed to be pathogenic.; SCV001142504: Experimental studies have shown that this missense change causes a significant reduction in enzyme activity and affinity for glucose-6-phosphate (PMID: 16607506).; SCV003929741: "In vitro functional studies indicate that R459L has a reduced catalytic efficiency of approximately 50% compared to wild type enzyme (Boonyuen et al., 2017);"
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R459C: Likely_pathogenic (ClinVar VariationId 1469858, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (23/23 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001360016.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	NM_001360016.2	MANE Select	c.1376G>T	p.Arg459Leu	missense	Exon 12 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.1466G>T	p.Arg489Leu	missense	Exon 12 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.1376G>T	p.Arg459Leu	missense	Exon 12 of 13	NP_001035810.1	P11413-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.1376G>T	p.Arg459Leu	missense	Exon 12 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.1376G>T	p.Arg459Leu	missense	Exon 12 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.1514G>T	p.Arg505Leu	missense	Exon 12 of 13	ENSP00000358633.2	P11413-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000250	AC:28	Hom:0	AN:112037	Cov:23
GnomAD2 exomes	AF: 0.000813	AC:148	Hom:	AN:181938	Cov:
GnomAD4 exome	AF: 0.000121	AC:133	Hom:0	AN:1097708	Cov:37
GnomAD4 genome	AF: 0.000250	AC:28	Hom:0	AN:112090	Cov:23
TOPMed (Bravo)	AF: 0.000276	AC:73	Hom:19	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000318	AC:2	Hom:0	AN:62928	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000100	AC:1	Hom:0	AN:101845	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.000953	40	41958	0.000224	15	66886
SCHEMA(Schizophrenia)	0.000467	52	111342	0.000186	35	188134

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (12)
5	-	-	not provided (5)
2	-	-	G6PD deficiency (2)
1	-	-	G6PD-related disorder (1)
1	-	-	Malaria, susceptibility to (1)
1	-	-	Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)
1	-	-	Type 2 diabetes mellitus (1)
-	-	-	G6PD AGRIGENTO (1)
-	-	-	G6PD CANTON (1)
-	-	-	G6PD GIFU (1)
-	-	-	G6PD TAIWAN-HAKKA (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	20
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.59
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.91	D
FuncVEP CTI	Pathogenic	0.74
GPN-Star LLR	N/A	-6.0
GPN-Star score	N/A	6.0
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.014	T
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	15/85	disease causing (ClinVar)
MutationAssessor	Benign	1.7	L
PhyloP100	Benign	3.7
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.70
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Varity_R	N/A	0.72
VESM-3B	Benign	-7.5

Showing 25 of 25 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.070
SpliceAI score (max)	Benign	0.050	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs72554665;

hg19: chrX-153760484;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar