dbSNP rs398123546: G6PD:p.Arg454Cys (chrX-154532390-G-A) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PM1PM5PP2PP3PP5_Very_StrongBS2_Supporting

The NM_001360016.2(G6PD):c.1360C>T(p.Arg454Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000678 in 1,210,242 control chromosomes in the GnomAD database, including 4 homozygotes. There are 16 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R454P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00017 ( 1 hom., 5 hem., cov: 25)

Exomes 𝑓: 0.000057 ( 3 hom. 11 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 7.55

Publications

102 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 13 ACMG points.

PM1

In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360016.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154532389-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1198343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.751

PP5

Variant X-154532390-G-A is Pathogenic according to our data. Variant chrX-154532390-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 93493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 5 XL geneVariant has number of hemizygotes 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.1360C>T	p.Arg454Cys	missense	Exon 11 of 13	NP_001346945.1	A0A384NL00
G6PD	NM_000402.4		c.1450C>T	p.Arg484Cys	missense	Exon 11 of 13	NP_000393.4	P11413-3
G6PD	NM_001042351.3		c.1360C>T	p.Arg454Cys	missense	Exon 11 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.1360C>T	p.Arg454Cys	missense	Exon 11 of 13	ENSP00000377192.3	P11413-1
G6PD	ENST00000696421.1		c.1360C>T	p.Arg454Cys	missense	Exon 11 of 13	ENSP00000512616.1	A0A8Q3SIS5
G6PD	ENST00000369620.6	TSL:5	c.1498C>T	p.Arg500Cys	missense	Exon 11 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes

AF:

0.000169

AC:

AN:

112662

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000354

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000281

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000562

Gnomad SAS

AF:

0.000720

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000148

AC:

AN:

182006

AF XY:

0.0000745

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000579

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000574

AC:

AN:

1097527

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

363079

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

26393

American (AMR)

AF:

0.000114

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.000232

AC:

AN:

30205

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54127

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40169

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

841839

Other (OTH)

AF:

0.000673

AC:

AN:

46076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000169

AC:

AN:

112715

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

34895

show subpopulations

African (AFR)

AF:

0.000353

AC:

AN:

31171

American (AMR)

AF:

0.000280

AC:

AN:

10696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.000564

AC:

AN:

3548

South Asian (SAS)

AF:

0.000722

AC:

AN:

2771

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6247

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53205

Other (OTH)

AF:

0.00

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000914

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.000107

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Anemia, nonspherocytic hemolytic, due to G6PD deficiency (7)

not provided (7)

G6PD deficiency (2)

Malaria, susceptibility to (1)

Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.81

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.75

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.7

PhyloP100

7.5

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MVP

1.0

MPC

2.4

ClinPred

0.33

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.94

gMVP

0.99

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.0

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