X-154532269-C-T

Variant names:

• chrX-154532269-C-T
• rs72554665
• NM_001360016.2:c.1376G>A
• G6PD p.Arg459His

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACMG Germline Pathogenicity v2019). PM1PM5PP5

The NM_001360016.2(G6PD):c.1376G>A (p.Arg459His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00001 (AC=11) in the gnomAD database across 1,097,707 control chromosomes, including 4 hemizygotes. The grpmax filtering allele frequency (95% CI) is 0.00000942. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). 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; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.69
• Publications: 6 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: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 17 pathogenic, 0 benign (OR vs. background: 175.0).
	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)
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

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>A p.Arg459His	missense	Exon 12 of 13	Prot: NP_001346945.1 UniProt:
	G6PD NM_000402.4		c.1466G>A p.Arg489His	missense	Exon 12 of 13	Prot: NP_000393.4 UniProt:
	G6PD NM_001042351.3		c.1376G>A p.Arg459His	missense	Exon 12 of 13	Prot: NP_001035810.1 UniProt:

G6PD NM_001360016.2

MANE Select

HGVSc / HGVSpc.1376G>Ap.Arg459His

Exon rankExon 12 of 13

missense

Prot: NP_001346945.1UniProt: A0A384NL00P11413-1

G6PD NM_000402.4

HGVSc / HGVSpc.1466G>Ap.Arg489His

Exon rankExon 12 of 13

missense

Prot: NP_000393.4UniProt: P11413-3

G6PD NM_001042351.3

HGVSc / HGVSpc.1376G>Ap.Arg459His

Exon rankExon 12 of 13

missense

Prot: NP_001035810.1UniProt: P11413-1A0A384NL00

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	G6PD ENST00000393562.10	TSL:1MANE Select	c.1376G>A p.Arg459His	missense	Exon 12 of 13	Prot: ENSP00000377192.3 UniProt:
	G6PD ENST00000696421.1		c.1376G>A p.Arg459His	missense	Exon 12 of 13	Prot: ENSP00000512616.1 UniProt:
	G6PD ENST00000369620.6	TSL:5	c.1514G>A p.Arg505His	missense	Exon 12 of 13	Prot: ENSP00000358633.2 UniProt:

G6PD ENST00000393562.10

TSL:1MANE Select

HGVSc / HGVSpc.1376G>Ap.Arg459His

Exon rankExon 12 of 13

missense

Prot: ENSP00000377192.3UniProt: P11413-1

G6PD ENST00000696421.1

HGVSc / HGVSpc.1376G>Ap.Arg459His

Exon rankExon 12 of 13

missense

Prot: ENSP00000512616.1UniProt: A0A8Q3SIS5

G6PD ENST00000369620.6

TSL:5

HGVSc / HGVSpc.1514G>Ap.Arg505His

Exon rankExon 12 of 13

missense

Prot: ENSP00000358633.2UniProt: 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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD2 exomes	AF: 0.0000110	AC:2	Hom:	AN:181938	Cov:
GnomAD4 exome	AF: 0.0000100	AC:11	Hom:0	AN:1097707	Cov:37
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:62928	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000200	AC:2	Hom:0	AN:101845	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000477	2	41958	0.00	0	66886
SCHEMA(Schizophrenia)	0.00	0	102302	0.0000110	2	182514

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

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Uncertain	0.90	D
FuncVEP CTI	Benign	0.26
GPN-Star LLR	N/A	-4.7
GPN-Star score	N/A	4.7
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	1.2	D
Mutation Taster	N/A	30/70	disease causing
MutationAssessor	Benign	1.9	L
PhyloP100	Benign	3.7
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.61
Sift	Benign	0.063	T
Sift4G	Benign	0.065	T
Varity_R	N/A	0.52
VESM-3B	Benign	-6.7

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Benign	0.030	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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 abnormal

3 no calibration

4 assays found for this variant.

Clinical calibration: 1 functionally abnormal (PS3), 0 functionally normal (BS3).

No calibration: 3 assays (score only).

Protein level

G6PD Combined Functional Scores

G6PD Combined Function Scores

• Gene: G6PD
• Score: 0.687 · p.Arg459His (assay numbering)

Classified as

PS3 strongFunctionally abnormalInvestigator-provided functional classes: pathogenic

+1 more calibration

PS3 strongFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: damaging

Protein level

G6PD Yeast Growth Scores

G6PD Yeast Growth

• Gene: G6PD
• Assay type: Cell proliferation assay with genetic complementation
• Mechanism: Molecular function
• Model system: Yeast
• Score: 0.641 · p.Arg459His (assay numbering)

No calibration data

This score is at approximately the 54th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

G6PD Yeast Growth (Control) Scores

G6PD Yeast Growth (Control)

• Gene: G6PD
• Assay type: Cell proliferation assay with genetic complementation
• Mechanism: Molecular function
• Model system: Yeast
• Score: 0.412 · p.Arg459His (assay numbering)

No calibration data

This score is at approximately the 29th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

G6PD VAMP-seq Scores

G6PD VAMP-seq

• Gene: G6PD
• Assay type: Flow cytometry assay
• Mechanism: Loss of function
• Model system: Immortalized human cells
• Score: 1.13 · p.Arg459His (assay numbering)

No calibration data

This score is at approximately the 85th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs72554665;

hg19: chrX-153760484;

COSMIC: COSV104682734;

COSMIC: COSV104682734;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar