dbSNP rs5030868: G6PD:p.Ser188Phe (chrX-154534419-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 15P and 3B. PS3PM1PP2PP5_Very_StrongBP4BS1_SupportingBS2_Supporting

The NM_001360016.2(G6PD):c.563C>T(p.Ser188Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00141 in 1,209,752 control chromosomes in the GnomAD database, including 23 homozygotes. There are 859 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as 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. Synonymous variant affecting the same amino acid position (i.e. S188S) has been classified as Likely benign.

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:56O:3

Conservation

PhyloP100: 5.54

Publications

246 publications found

Variant links:

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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
G6PD deficiency
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
class I glucose-6-phosphate dehydrogenase deficiency
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

G6PD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: 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).

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001360016.2

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 185 curated pathogenic missense variants (we use a threshold of 10). The gene has 42 curated benign missense variants. Gene score misZ: 2.0008 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency, anemia, nonspherocytic hemolytic, due to G6PD deficiency.

PP5

Variant X-154534419-G-A is Pathogenic according to our data. Variant chrX-154534419-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 100057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.012398928). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00148 (1624/1097898) while in subpopulation MID AF = 0.0435 (180/4135). AF 95% confidence interval is 0.0383. There are 21 homozygotes in GnomAdExome4. There are 822 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 XL geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

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

RefSeq Transcripts

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

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:

AN:

111798

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00226

AC XY:

822

AN XY:

363276

show subpopulations

African (AFR)

AF:

0.000303

AC:

AN:

26401

American (AMR)

AF:

0.0000284

AC:

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

106

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.0189

AC:

1021

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000724

AC:

AN:

111854

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

34102

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

30815

American (AMR)

AF:

0.00

AC:

AN:

10658

Ashkenazi Jewish (ASJ)

AF:

0.00604

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3528

South Asian (SAS)

AF:

0.0149

AC:

AN:

2677

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6162

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000208

AC:

AN:

52952

Other (OTH)

AF:

0.00462

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.000559

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.00310

AC:

376

EpiCase

AF:

0.00147

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Anemia, nonspherocytic hemolytic, due to G6PD deficiency (31)

not provided (13)

G6PD deficiency (3)

Malaria, susceptibility to (2)

Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (2)

G6PD deficient hemolytic anemia (1)

G6PD-related disorder (1)

Hemolytic anemia, G6PD deficient (favism) (1)

Inborn genetic diseases (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

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.012

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.4

PhyloP100

5.5

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.81

Sift

Uncertain

0.017

Sift4G

Uncertain

0.0080

Polyphen

0.022

Vest4

0.56

MVP

0.99

MPC

0.20

ClinPred

0.13

GERP RS

5.7

Varity_R

0.90

gMVP

0.93

Mutation Taster

=16/84

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over