chrX-101407856-A-C
Variant summary
Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000169.3(GLA):c.48T>G(p.Leu16Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,210,031 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 89 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). Synonymous variant affecting the same amino acid position (i.e. L16L) has been classified as Likely benign.
Frequency
Consequence
NM_000169.3 synonymous
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Benign. The variant received -14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000116 AC: 13AN: 112226Hom.: 0 Cov.: 23 show subpopulations
GnomAD2 exomes AF: 0.000196 AC: 36AN: 183415 AF XY: 0.0000737 show subpopulations
GnomAD4 exome AF: 0.000307 AC: 337AN: 1097748Hom.: 0 Cov.: 31 AF XY: 0.000234 AC XY: 85AN XY: 363104 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000116 AC: 13AN: 112283Hom.: 0 Cov.: 23 AF XY: 0.000116 AC XY: 4AN XY: 34425 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
This variant is associated with the following publications: (PMID: 26866599) -
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GLA: BP4, BP7, BS2 -
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Fabry disease Benign:6
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
The c.48T>G variant in GLA has not been previously reported in individuals with Fabry disease, and has been identified in 0.039% (36/92630) of European (non-Finnish) chromosomes, including 5 hemizygotes, 0.019% (1/5335) of other chromosomes, and 0.011% (3/28053) of Latino chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201449986). This variant has also been reported in ClinVar as likely bengin by the Laboratory for Molecular Medicine (Partners Healthcare), GeneDx, and Invitae and a VUS by Illumina Clinical Services Laboratory (ID:42455). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP7 (Richards 2015). -
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Hypertrophic cardiomyopathy Uncertain:1Benign:1
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not specified Benign:2
Leu16Leu in exon 1 of GLA: This variant is not expected to have clinical signifi cance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 1/6728 European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.ed/EVS/;). Leu16Leu in exon 1 of GLA (allele frequency = 1/6728) ** -
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GLA-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at