Genetic Variant NM_001360016.2:c.542A>T (chrX-154534440-T-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 11P and 2B. PM1PP2PP5_Very_StrongBP4BS2_Supporting

The NM_001360016.2(G6PD):c.542A>T(p.Asp181Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000777 in 1,209,769 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.000041 ( 0 hom. 15 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 7.78

Publications

56 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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-154534440-T-A is Pathogenic according to our data. Variant chrX-154534440-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.16829187). . Strength limited to SUPPORTING due to the PP5.

BS2

High Hemizygotes in GnomAd4 at 7 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
G6PD	NM_001360016.2	MANE Select	c.542A>T	p.Asp181Val	missense	Exon 6 of 13	NP_001346945.1
G6PD	NM_000402.4		c.632A>T	p.Asp211Val	missense	Exon 6 of 13	NP_000393.4
G6PD	NM_001042351.3		c.542A>T	p.Asp181Val	missense	Exon 6 of 13	NP_001035810.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
G6PD	ENST00000393562.10	TSL:1 MANE Select	c.542A>T	p.Asp181Val	missense	Exon 6 of 13	ENSP00000377192.3
G6PD	ENST00000696421.1		c.542A>T	p.Asp181Val	missense	Exon 6 of 13	ENSP00000512616.1
G6PD	ENST00000369620.6	TSL:5	c.542A>T	p.Asp181Val	missense	Exon 6 of 13	ENSP00000358633.2

Frequencies

GnomAD3 genomes

AF:

0.000438

AC:

AN:

111781

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00103

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:

0.000136

AC:

AN:

183162

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00106

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1097988

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363384

show subpopulations

African (AFR)

AF:

0.000871

AC:

AN:

26402

American (AMR)

AF:

0.000313

AC:

AN:

35195

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54141

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40452

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841983

Other (OTH)

AF:

0.000174

AC:

AN:

46089

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000438

AC:

AN:

111781

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

33999

show subpopulations

African (AFR)

AF:

0.00124

AC:

AN:

30751

American (AMR)

AF:

0.00103

AC:

AN:

10657

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52931

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.0000754

Hom.:

Bravo

AF:

0.000536

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

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

G6PD deficiency (1)

Malaria, susceptibility to (1)

G6PD MALAGA (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.17

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

-0.29

PhyloP100

7.8

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.61

Sift

Benign

0.073

Sift4G

Benign

0.16

Polyphen

0.0080

Vest4

0.68

MVP

1.0

MPC

0.29

ClinPred

0.057

GERP RS

5.7

Varity_R

0.71

gMVP

0.80

Mutation Taster

=59/41

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