14-87993008-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000153.4(GALC):c.157C>T(p.Arg53Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,540,776 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R53R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000153.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.157C>T | p.Arg53Trp | missense_variant | 1/17 | ENST00000261304.7 | |
GALC | NM_001201401.2 | c.157C>T | p.Arg53Trp | missense_variant | 1/16 | ||
GALC | NM_001201402.2 | c.117+375C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.157C>T | p.Arg53Trp | missense_variant | 1/17 | 1 | NM_000153.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000140 AC: 2AN: 142732Hom.: 0 AF XY: 0.0000251 AC XY: 2AN XY: 79534
GnomAD4 exome AF: 0.0000101 AC: 14AN: 1388626Hom.: 0 Cov.: 33 AF XY: 0.0000146 AC XY: 10AN XY: 687026
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74334
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 27, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALC protein function. ClinVar contains an entry for this variant (Variation ID: 557770). This missense change has been observed in individual(s) with Krabbe disease (PMID: 21824559). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 53 of the GALC protein (p.Arg53Trp). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 06, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at