X-101398920-G-T
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000169.3(GLA):c.666C>A(p.Tyr222*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,169 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )
Consequence
GLA
NM_000169.3 stop_gained
NM_000169.3 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 1.58
Publications
4 publications found
Genes affected
GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]
RPL36A-HNRNPH2 (HGNC:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-101398920-G-T is Pathogenic according to our data. Variant chrX-101398920-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000169.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLA | NM_000169.3 | MANE Select | c.666C>A | p.Tyr222* | stop_gained | Exon 5 of 7 | NP_000160.1 | ||
| GLA | NM_001406747.1 | c.789C>A | p.Tyr263* | stop_gained | Exon 6 of 8 | NP_001393676.1 | |||
| GLA | NM_001406748.1 | c.666C>A | p.Tyr222* | stop_gained | Exon 5 of 6 | NP_001393677.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLA | ENST00000218516.4 | TSL:1 MANE Select | c.666C>A | p.Tyr222* | stop_gained | Exon 5 of 7 | ENSP00000218516.4 | ||
| RPL36A-HNRNPH2 | ENST00000409170.3 | TSL:4 | c.300+3463G>T | intron | N/A | ENSP00000386655.4 | |||
| GLA | ENST00000649178.1 | c.789C>A | p.Tyr263* | stop_gained | Exon 6 of 8 | ENSP00000498186.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome AF: 9.15e-7 AC: 1AN: 1093169Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 358887 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1093169
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
358887
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
26305
American (AMR)
AF:
AC:
0
AN:
35201
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
19347
East Asian (EAS)
AF:
AC:
0
AN:
30186
South Asian (SAS)
AF:
AC:
0
AN:
53979
European-Finnish (FIN)
AF:
AC:
0
AN:
40528
Middle Eastern (MID)
AF:
AC:
0
AN:
3749
European-Non Finnish (NFE)
AF:
AC:
1
AN:
837972
Other (OTH)
AF:
AC:
0
AN:
45902
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<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
GnomAD4 genome
Cov.:
23
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
4
-
-
Fabry disease (4)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
PhyloP100
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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