X-154535187-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBS2_Supporting

The NM_001360016.2(G6PD):c.466G>A(p.Glu156Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000868 in 1,209,283 control chromosomes in the GnomAD database, including 2 homozygotes. There are 34 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000081 ( 2 hom. 29 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:1O:1

Conservation

PhyloP100: 0.964

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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). GenCC associations: The gene is linked to class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency, anemia, nonspherocytic hemolytic, due to G6PD deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.060296565).

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2 link	c.466G>A	p.Glu156Lys	missense_variant	Exon 5 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 link	c.556G>A	p.Glu186Lys	missense_variant	Exon 5 of 13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 link	c.466G>A	p.Glu156Lys	missense_variant	Exon 5 of 13		NP_001035810.1	P11413-1A0A384NL00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10 link	c.466G>A	p.Glu156Lys	missense_variant	Exon 5 of 13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

111791

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000390

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.000666

GnomAD2 exomes

AF:

0.000273

AC:

AN:

183269

AF XY:

0.000266

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000811

AC:

AN:

1097438

Hom.:

Cov.:

AF XY:

0.0000799

AC XY:

AN XY:

363082

show subpopulations

Gnomad4 AFR exome

AF:

0.000607

AC:

AN:

26379

Gnomad4 AMR exome

AF:

0.000966

AC:

AN:

35207

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19382

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30205

Gnomad4 SAS exome

AF:

0.000444

AC:

AN:

54113

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40527

Gnomad4 NFE exome

AF:

0.0000119

AC:

AN:

841957

Gnomad4 Remaining exome

AF:

0.0000652

AC:

AN:

46033

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000143

AC:

AN:

111845

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

AN XY:

34049

show subpopulations

Gnomad4 AFR

AF:

0.000389

AC:

0.000389269

AN:

0.000389269

Gnomad4 AMR

AF:

0.000188

AC:

0.000187882

AN:

0.000187882

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000189

AC:

0.0000188772

AN:

0.0000188772

Gnomad4 OTH

AF:

0.000658

AC:

0.000657895

AN:

0.000657895

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000848

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000313

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:1Uncertain:1Benign:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 12, 2022

Dunham Lab, University of Washington

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Variant found in hemizygotes with G6PD deficiency (PP4). Decreased activity in red blood cells of hemizygotes (21-25%) (PS3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.949 (odds of pathogenicity 168.4, Prior_P 0.1). -

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: G6PD c.556G>A (p.Glu186Lys) results in a conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 183269 control chromosomes in the gnomAD database, including 1 homozygote and 18 hemizygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00027 vs 0.29), allowing no conclusion about variant significance. c.556G>A has been reported in the literature in asymptomatic individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Villiamy_1988, Nafa_1994, Aggarwal_2019). These reports do not provide unequivocal conclusions about association of the variant with Glucose 6 Phosphate Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 3393536, 32680472, 7959686, 31602632). ClinVar contains an entry for this variant (Variation ID: 10364). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Feb 24, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

G6PD ILESHA

Other:1

May 24, 2017

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Uncertain

0.70

D;D;D;.;D;.;D

FATHMM_MKL

Benign

0.027

LIST_S2

Uncertain

0.97

.;.;D;D;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.060

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

0.49

N;N;N;N;.;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.88

.;.;N;N;N;N;N

REVEL

Uncertain

0.55

Sift

Benign

1.0

.;.;T;T;T;T;T

Sift4G

Benign

1.0

T;.;T;T;.;.;.

Polyphen

0.0050

B;B;B;.;.;.;.

Vest4

0.20

MVP

0.99

MPC

0.20

ClinPred

0.0018

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.54

gMVP

0.56

Mutation Taster

=76/24

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over