X-154532969-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP5BP4BS2_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
NM_001360016.2 missense
Scores
5
2
6
Clinical Significance
Conservation
PhyloP100: 5.29
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001360016.2
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 id is 10405.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=2, Uncertain_significance=3}. Variant chrX-154532969-G-A is described in Lovd as [Pathogenic]. Variant chrX-154532969-G-A is described in Lovd as [Pathogenic].
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.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
G6PD | NM_001360016.2 | c.1024C>T | p.Leu342Phe | missense_variant | 9/13 | ENST00000393562.10 | |
G6PD | NM_000402.4 | c.1114C>T | p.Leu372Phe | missense_variant | 9/13 | ||
G6PD | NM_001042351.3 | c.1024C>T | p.Leu342Phe | missense_variant | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
G6PD | ENST00000393562.10 | c.1024C>T | p.Leu342Phe | missense_variant | 9/13 | 1 | NM_001360016.2 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000444 AC: 5AN: 112603Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 34767
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GnomAD3 exomes AF: 0.000137 AC: 25AN: 183026Hom.: 0 AF XY: 0.000104 AC XY: 7AN XY: 67564
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GnomAD4 exome AF: 0.0000191 AC: 21AN: 1098212Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 5AN XY: 363580
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GnomAD4 genome AF: 0.0000444 AC: 5AN: 112655Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 34829
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:2Uncertain:2
Pathogenic, criteria provided, single submitter | curation | Dunham Lab, University of Washington | Aug 12, 2022 | Variant found in unrelated hemizygotes with deficiency, some with anemia (PS4_M, PP4). Also found in two heterozygous sisters with deficiency who inherited this variant (c.1024C>T) from father and c.383T>C from mother (PP1). Decreased activity in red blood cells (2-39%) (PS3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 21, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 12, 2021 | This sequence change replaces leucine with phenylalanine at codon 342 of the G6PD protein (p.Leu342Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 8364584, 10502785, 16329560, 20203002, 30045279, 30315739). This variant is also known as C13184T or Chinese-5. ClinVar contains an entry for this variant (Variation ID: 10405). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 17, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 28, 2017 | - - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 15, 2024 | Variant summary: NPC1 c.1114C>T (p.Arg372Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251162 control chromosomes. c.1114C>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
G6PD deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 15, 2024 | Variant summary: G6PD c.1114C>T (p.Leu372Phe, also known as Chinese-5) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 183026 control chromosomes with 7 hemizygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00014 vs 0.29), allowing no conclusion about variant significance. c.1114C>T has been reported in the literature in many individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (example, Wang_2021, Fu_2018). These data indicate that the variant is very likely to be associated with disease. At least 7 studies report experimental evidence evaluating an impact on protein function using hemizygote cells, the average G6PD activity appeared to be 30-40% of normal activity (Geck_2023). The following publications have been ascertained in the context of this evaluation (PMID: 29339739, 36681081, 34659341). ClinVar contains an entry for this variant (Variation ID: 10405). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Metachromatic leukodystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 15, 2024 | Variant summary: ARSA c.1114C>T (p.Arg372Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250080 control chromosomes. c.1114C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Biffi_2008, Heinisch_1995, Fumagalli_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
G6PD MAHIDOL-LIKE Other:1
other, no assertion criteria provided | literature only | OMIM | Apr 18, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Pathogenic
D;D;D;.
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;L;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;.;T;T
Polyphen
P;P;P;.
Vest4
MVP
MPC
1.5
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at