14-87988514-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001424074.1(GALC):c.-144C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000192 in 1,611,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001424074.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.205C>T | p.Arg69* | stop_gained | Exon 2 of 17 | ENST00000261304.7 | NP_000144.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151994Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248890Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135118
GnomAD4 exome AF: 0.0000199 AC: 29AN: 1459096Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13AN XY: 726106
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151994Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74248
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:5
Variant summary: The GALC c.205C>T (p.Arg69X) variant results in a premature termination codon, predicted to cause a truncated or absent GALC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/119986 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361). The variant was reported in multiple affected individuals in the literature, and was shown to result in <10% GALC activity in a functional study where the variant was expressed in COS1 cells (Saavedra-Matiz_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
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This sequence change creates a premature translational stop signal (p.Arg69*) in the GALC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs771111145, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Krabbe disease (PMID: 20886637). ClinVar contains an entry for this variant (Variation ID: 195020). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:3
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Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease, and published functional studies support a null allele (PMID: 27638593); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.157C>T, p.R53* due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 25525159, 27638593, 20886637) -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at