Genetic Variant NM_001360016.2:c.1024C>T (chrX-154532969-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PP2PP5BP4BS2_Supporting

The NM_001360016.2(G6PD):c.1024C>T(p.Leu342Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000215 in 1,210,867 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 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 0.000044 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000019 ( 0 hom. 5 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:3O:1

Conservation

PhyloP100: 5.29

Publications

94 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.

PP5

Variant X-154532969-G-A is Pathogenic according to our data. Variant chrX-154532969-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10405.

BP4

Computational evidence support a benign effect (MetaRNN=0.13903645). . Strength limited to SUPPORTING due to the PP5.

BS2

High Hemizygotes in GnomAdExome4 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.1024C>T	p.Leu342Phe	missense	Exon 9 of 13	NP_001346945.1	A0A384NL00
G6PD	NM_000402.4		c.1114C>T	p.Leu372Phe	missense	Exon 9 of 13	NP_000393.4	P11413-3
G6PD	NM_001042351.3		c.1024C>T	p.Leu342Phe	missense	Exon 9 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.1024C>T	p.Leu342Phe	missense	Exon 9 of 13	ENSP00000377192.3	P11413-1
G6PD	ENST00000696421.1		c.1024C>T	p.Leu342Phe	missense	Exon 9 of 13	ENSP00000512616.1	A0A8Q3SIS5
G6PD	ENST00000369620.6	TSL:5	c.1162C>T	p.Leu388Phe	missense	Exon 9 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes

AF:

0.0000444

AC:

AN:

112603

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00140

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:

0.000137

AC:

AN:

183026

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00166

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000191

AC:

AN:

1098212

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363580

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.000629

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842135

Other (OTH)

AF:

0.0000217

AC:

AN:

46097

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:

0.0000444

AC:

AN:

112655

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34829

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31090

American (AMR)

AF:

0.00

AC:

AN:

10784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00141

AC:

AN:

3550

South Asian (SAS)

AF:

0.00

AC:

AN:

2703

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6293

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53139

Other (OTH)

AF:

0.00

AC:

AN:

1544

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

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:

0.0000339

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

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 (5)

not provided (3)

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

G6PD deficiency (1)

G6PD MAHIDOL-LIKE (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.61

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.14

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.6

PhyloP100

5.3

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.70

Sift

Benign

0.14

Sift4G

Benign

0.18

Polyphen

0.69

Vest4

0.77

MVP

1.0

MPC

1.5

ClinPred

0.12

GERP RS

4.0

Varity_R

0.67

gMVP

0.98

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

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

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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