chrX-154532268-AC-GT

Variant names:

• chrX-154532268-AC-GT
• NM_001360016.2:c.1376_1377delGTinsAC
• G6PD p.Arg459His

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PS1_ModeratePM1PM2PM5

The NM_001360016.2(G6PD):c.1376_1377delGTinsAC (p.Arg459His) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 23)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 0 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: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, 0-star ClinVar pathogenic — moderate (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 0 stars).
	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).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00644) — PM2 moderate.
	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)

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.1376_1377delGTinsAC p.Arg459His	missense	N/A	Prot: NP_001346945.1 UniProt:
	G6PD NM_000402.4		c.1466_1467delGTinsAC p.Arg489His	missense	N/A	Prot: NP_000393.4 UniProt:
	G6PD NM_001042351.3		c.1376_1377delGTinsAC p.Arg459His	missense	N/A	Prot: NP_001035810.1 UniProt:

G6PD NM_001360016.2

MANE Select

HGVSc / HGVSpc.1376_1377delGTinsACp.Arg459His

Exon rankN/A

missense

Prot: NP_001346945.1UniProt: A0A384NL00P11413-1

G6PD NM_000402.4

HGVSc / HGVSpc.1466_1467delGTinsACp.Arg489His

Exon rankN/A

missense

Prot: NP_000393.4UniProt: P11413-3

G6PD NM_001042351.3

HGVSc / HGVSpc.1376_1377delGTinsACp.Arg459His

Exon rankN/A

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.1376_1377delGTinsAC p.Arg459His	missense	N/A	Prot: ENSP00000377192.3 UniProt:
	G6PD ENST00000696421.1		c.1376_1377delGTinsAC p.Arg459His	missense	N/A	Prot: ENSP00000512616.1 UniProt:
	G6PD ENST00000369620.6	TSL:5	c.1514_1515delGTinsAC p.Arg505His	missense	N/A	Prot: ENSP00000358633.2 UniProt:

G6PD ENST00000393562.10

TSL:1MANE Select

HGVSc / HGVSpc.1376_1377delGTinsACp.Arg459His

Exon rankN/A

missense

Prot: ENSP00000377192.3UniProt: P11413-1

G6PD ENST00000696421.1

HGVSc / HGVSpc.1376_1377delGTinsACp.Arg459His

Exon rankN/A

missense

Prot: ENSP00000512616.1UniProt: A0A8Q3SIS5

G6PD ENST00000369620.6

TSL:5

HGVSc / HGVSpc.1514_1515delGTinsACp.Arg505His

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	3.7

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chrX-153760483;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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