NM_001360016.2:c.493A>G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PP2PP5_Very_Strong

The NM_001360016.2(G6PD):c.493A>G(p.Asn165Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 1,210,034 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 4.92

Publications

9 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.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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-154534489-T-C is Pathogenic according to our data. Variant chrX-154534489-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.493A>G	p.Asn165Asp	missense	Exon 6 of 13	NP_001346945.1	A0A384NL00
G6PD	NM_000402.4		c.583A>G	p.Asn195Asp	missense	Exon 6 of 13	NP_000393.4	P11413-3
G6PD	NM_001042351.3		c.493A>G	p.Asn165Asp	missense	Exon 6 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.493A>G	p.Asn165Asp	missense	Exon 6 of 13	ENSP00000377192.3	P11413-1
G6PD	ENST00000696421.1		c.493A>G	p.Asn165Asp	missense	Exon 6 of 13	ENSP00000512616.1	A0A8Q3SIS5
G6PD	ENST00000369620.6	TSL:5	c.493A>G	p.Asn165Asp	missense	Exon 6 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112302

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:

0.00113

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:

0.0000495

AC:

AN:

181972

AF XY:

0.0000598

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000650

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097732

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35204

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:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40057

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842106

Other (OTH)

AF:

0.0000868

AC:

AN:

46093

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112302

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30903

American (AMR)

AF:

0.00

AC:

AN:

10727

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2662

East Asian (EAS)

AF:

0.00113

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6231

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53051

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.00

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000824

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Malaria, susceptibility to (1)

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

not provided (1)

not specified (1)

G6PD TAIWAN-HAKKA 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.53

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.7

PhyloP100

4.9

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.67

Sift

Benign

0.069

Sift4G

Benign

0.066

Polyphen

0.0060

Vest4

0.69

MutPred

0.85

Loss of sheet (P = 0.1398)

MVP

0.97

MPC

0.25

ClinPred

0.14

GERP RS

5.7

Varity_R

0.94

gMVP

0.84

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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