NM_000169.3:c.718_719delAA
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.718_719delAA(p.Lys240GlufsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,569 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K240K) has been classified as Likely benign. 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 frameshift
NM_000169.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.68
Publications
22 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-101398866-CTT-C is Pathogenic according to our data. Variant chrX-101398866-CTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 222371.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
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLA | MANE Select | c.718_719delAA | p.Lys240GlufsTer9 | frameshift | Exon 5 of 7 | NP_000160.1 | P06280 | ||
| GLA | c.841_842delAA | p.Lys281GlufsTer9 | frameshift | Exon 6 of 8 | NP_001393676.1 | A0A3B3IUC4 | |||
| GLA | c.718_719delAA | p.Lys240GlufsTer9 | frameshift | Exon 5 of 6 | NP_001393677.1 | A0A6Q8PHD1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLA | TSL:1 MANE Select | c.718_719delAA | p.Lys240GlufsTer9 | frameshift | Exon 5 of 7 | ENSP00000218516.4 | P06280 | ||
| RPL36A-HNRNPH2 | TSL:4 | c.300+3411_300+3412delTT | intron | N/A | ENSP00000386655.4 | H7BZ11 | |||
| GLA | c.841_842delAA | p.Lys281GlufsTer9 | frameshift | Exon 6 of 8 | ENSP00000498186.1 | A0A3B3IUC4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome AF: 9.14e-7 AC: 1AN: 1093569Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 359013 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1093569
Hom.:
AF XY:
AC XY:
0
AN XY:
359013
show subpopulations
African (AFR)
AF:
AC:
0
AN:
26302
American (AMR)
AF:
AC:
0
AN:
35204
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
19358
East Asian (EAS)
AF:
AC:
0
AN:
30191
South Asian (SAS)
AF:
AC:
0
AN:
54047
European-Finnish (FIN)
AF:
AC:
0
AN:
40530
Middle Eastern (MID)
AF:
AC:
0
AN:
4102
European-Non Finnish (NFE)
AF:
AC:
1
AN:
837912
Other (OTH)
AF:
AC:
0
AN:
45923
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.725
Heterozygous variant carriers
0
0
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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30-35
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
6
-
-
Fabry disease (6)
4
-
-
not provided (4)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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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