Genetic Variant NM_001360016.2:c.680G>A (chrX-154534125-C-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3PM1PM5PP2PP3_ModeratePP5BS2_Supporting

The NM_001360016.2(G6PD):c.680G>A(p.Arg227Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000636 in 1,210,410 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002599343: Decreased activity in red blood cells (35%) (PS3).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000063 ( 0 hom. 24 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2O:1

Conservation

PhyloP100: 5.50

Publications

58 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 11 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002599343: Decreased activity in red blood cells (35%) (PS3).

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001360016.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154534125-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10387.Status of the report is no_assertion_criteria_provided, 0 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 class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency, anemia, nonspherocytic hemolytic, due to G6PD deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

PP5

Variant X-154534125-C-T is Pathogenic according to our data. Variant chrX-154534125-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10395.

BS2

High Hemizygotes in GnomAd4 at 6 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.680G>A	p.Arg227Gln	missense	Exon 7 of 13	NP_001346945.1	A0A384NL00
G6PD	NM_000402.4		c.770G>A	p.Arg257Gln	missense	Exon 7 of 13	NP_000393.4	P11413-3
G6PD	NM_001042351.3		c.680G>A	p.Arg227Gln	missense	Exon 7 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.680G>A	p.Arg227Gln	missense	Exon 7 of 13	ENSP00000377192.3	P11413-1
G6PD	ENST00000696421.1		c.680G>A	p.Arg227Gln	missense	Exon 7 of 13	ENSP00000512616.1	A0A8Q3SIS5
G6PD	ENST00000369620.6	TSL:5	c.680G>A	p.Arg227Gln	missense	Exon 7 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes

AF:

0.0000713

AC:

AN:

112270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000750

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000491

AC:

AN:

183199

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000628

AC:

AN:

1098140

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

363506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.000170

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40502

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.0000653

AC:

AN:

842095

Other (OTH)

AF:

0.000152

AC:

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000713

AC:

AN:

112270

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

34432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30904

American (AMR)

AF:

0.000750

AC:

AN:

10672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3562

South Asian (SAS)

AF:

0.00

AC:

AN:

2717

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53132

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000235

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Anemia, nonspherocytic hemolytic, due to G6PD deficiency (4)

G6PD deficiency (1)

not specified (1)

G6PD MEXICO CITY (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

PhyloP100

5.5

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0030

Polyphen

0.94

Vest4

0.75

MVP

1.0

MPC

1.3

ClinPred

0.43

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.98

Mutation Taster

=45/55

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over