rs5030868

Variant names:

• chrX-154534419-G-A
• rs5030868
• NM_001360016.2:c.563C>T
• G6PD p.Ser188Phe

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PS3PP3_ModeratePP5_Strong

The NM_001360016.2(G6PD):c.563C>T (p.Ser188Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00141 (AC=1,705) in the gnomAD database across 1,209,752 control chromosomes, including 23 homozygotes and 859 hemizygotes. The grpmax filtering allele frequency (95% CI) is 0.0383. 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: "SCV000321681: Published functional studies demonstrate decreased enzyme activity in circulating erythrocytes, increased affinity for G6P, and decreased in vitro thermostability (Vulliamy et al., 1998);" and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S188= (synonymous): Likely_benign (ClinVar VariationId 1107399, 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: 𝑓 0.00072 (2 hom., 37 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (21 hom. 822 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:64 O:3
• Conservation: PhyloP100: 5.54
• Publications: 246 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

Our verdict: Pathogenic. The variant received 10 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000321681: Published functional studies demonstrate decreased enzyme activity in circulating erythrocytes, increased affinity for G6P, and decreased in vitro thermostability (Vulliamy et al., 1998);; SCV000885494: Functional analyses of the variant protein shows decreased enzyme activity, increased affinity for G6P and decreased in vitro thermostability (Moiz 2012, Molou 2014, Vulliamy 1988).; SCV000647802: Experimental studies have shown that this missense change affects G6PD function (PMID: 3393536, 22906047, 24460025).; SCV002073219: Experimental studies have shown that this missense change affects G6PD function (Molouet. al., 2014).; SCV002572646: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22906047, 24460025, 3393536).; SCV002599337: Decreased activity in red blood cells (0-33%) (PS3).; SCV003921882: "This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to result in highly impaired enzyme activity (PMID: 3393536, PMID: 7211845)."; SCV006557123: Experimental studies support this variant is deleterious.; SCV000915299: The c.563C>T variant resulted in 0-7% residual enzyme activity in red blood cells compared to wild type and caused decreased thermostability and reduced catalytic activity (PMID: 3393536).; SCV004122524: The most pronounced variant effect results in <10% of normal activity (Vulliamy_1988).; SCV001443686: Functional studies demonstrate decreased enzyme activity in the circulating erythrocytes of individuals with this variant, increased affinity for G6P and decreased in vitro thermostability (PMID: 9342374, 3393536).
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: 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 (64/64 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.563C>T	p.Ser188Phe	missense	Exon 6 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.653C>T	p.Ser218Phe	missense	Exon 6 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.563C>T	p.Ser188Phe	missense	Exon 6 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.563C>T	p.Ser188Phe	missense	Exon 6 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.563C>T	p.Ser188Phe	missense	Exon 6 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.563C>T	p.Ser188Phe	missense	Exon 6 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.000733 AC: 82 AN: 111798 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00604

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.00468

GnomAD2 exomes AF: 0.00255 AC: 468 AN: 183257 AF XY: 0.00375

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00601

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000770

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00148 AC: 1624 AN: 1097898 Hom.: 21 Cov.: 32 AF XY: 0.00226 AC XY: 822 AN XY: 363276

African (AFR) AF: 0.000303 AC: 8 AN: 26401

American (AMR) AF: 0.0000284 AC: 1 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 106 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0189 AC: 1021 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40482

Middle Eastern (MID) AF: 0.0435 AC: 180 AN: 4135

European-Non Finnish (NFE) AF: 0.000189 AC: 159 AN: 841880

Other (OTH) AF: 0.00323 AC: 149 AN: 46085

GnomAD4 genome AF: 0.000724 AC: 81 AN: 111854 Hom.: 2 Cov.: 23 AF XY: 0.00108 AC XY: 37 AN XY: 34102

African (AFR) AF: 0.000130 AC: 4 AN: 30815

American (AMR) AF: 0.00 AC: 0 AN: 10658

Ashkenazi Jewish (ASJ) AF: 0.00604 AC: 16 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.0149 AC: 40 AN: 2677

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6162

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.000208 AC: 11 AN: 52952

Other (OTH) AF: 0.00462 AC: 7 AN: 1515

Alfa AF: 0.00118 Hom.: 66

Bravo AF: 0.000559

EpiCase AF: 0.00147

EpiControl AF: 0.00119

Local populations

Turkish Variome AF: 0.00858 AC: 57 AN: 6642 Hom.: 18

ABraOM SABE-WGS-1171 AF: 0.00104 AC: 2 AN: 1916 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
35	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (35)
14	-	-	not provided (14)
5	-	-	G6PD deficiency (5)
2	-	-	Malaria, susceptibility to (2)
2	-	-	Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (2)
1	-	-	G6PD deficient hemolytic anemia (1)
1	-	-	G6PD-related disorder (1)
1	-	-	Granulomatous disease, chronic, X-linked (1)
1	-	-	Hemolytic anemia, G6PD deficient (favism) (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	See cases (1)
-	-	-	G6PD CAGLIARI (1)
-	-	-	G6PD MEDITERRANEAN (1)
-	-	-	G6PD SASSARI (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.012	T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.5
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0080	D
Varity_R		0.90
gMVP		0.93
Mutation Taster		=16/84	disease causing (ClinVar)

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

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

Other links and lift over

dbSNP: rs5030868;

hg19: chrX-153762634;

COSMIC: COSV63704212;

COSMIC: COSV63704212;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar