Variant X-154532990-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The ENST00000393562.10(G6PD):c.1003G>T(p.Ala335Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A335D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 24)

Consequence

G6PD
ENST00000393562.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.969

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000393562.10

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154532989-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1068217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
G6PD	NM_001360016.2 linkuse as main transcript	c.1003G>T	p.Ala335Ser	missense_variant	9/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 linkuse as main transcript	c.1093G>T	p.Ala365Ser	missense_variant	9/13		NP_000393.4
G6PD	NM_001042351.3 linkuse as main transcript	c.1003G>T	p.Ala335Ser	missense_variant	9/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10 linkuse as main transcript	c.1003G>T	p.Ala335Ser	missense_variant	9/13	1	NM_001360016.2	ENSP00000377192	P4	P11413-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000548

AC:

AN:

182482

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;D;D;.;D

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.96

.;.;D;D;T

M_CAP

Pathogenic

0.62

MetaRNN

Uncertain

0.67

D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.5

L;L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.63

.;.;N;N;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

.;.;D;D;D

Sift4G

Uncertain

0.0030

D;.;D;D;.

Polyphen

0.10

B;B;B;.;.

Vest4

0.43

MutPred

0.66

Gain of glycosylation at A335 (P = 0.0103);Gain of glycosylation at A335 (P = 0.0103);Gain of glycosylation at A335 (P = 0.0103);.;.;

MVP

0.89

MPC

1.7

ClinPred

0.55

GERP RS

5.8

Varity_R

0.74

gMVP

0.85

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over