chr14-87986552-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000153.4(GALC):c.379C>T(p.Arg127Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000434 in 1,613,600 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
GALC
NM_000153.4 stop_gained
NM_000153.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 5.31
Genes affected
GALC (HGNC:4115): (galactosylceramidase) This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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 14-87986552-G-A is Pathogenic according to our data. Variant chr14-87986552-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 429982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.379C>T | p.Arg127Ter | stop_gained | 4/17 | ENST00000261304.7 | NP_000144.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.379C>T | p.Arg127Ter | stop_gained | 4/17 | 1 | NM_000153.4 | ENSP00000261304 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152010Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249360Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135276
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GnomAD4 exome AF: 0.0000452 AC: 66AN: 1461590Hom.: 0 Cov.: 30 AF XY: 0.0000426 AC XY: 31AN XY: 727114
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152010Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74240
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 18, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with Krabbe disease [PMID 20886637] - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Apr 27, 2023 | PVS1, PS3, PM2 - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 20, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg127*) 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 (rs200532368, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with autosomal recessive Krabbe disease (PMID: 20886637, 21824559, 27638593). This variant is also known as p.R111X. ClinVar contains an entry for this variant (Variation ID: 429982). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 28, 2016 | Variant summary: The c.379C>T (p.Arg127*) variant in GALC gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant has been reported in several affected individuals presented with infantile form of Krabbe via published reports. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0032% exclusively in individuals of European descent (0.06%). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in GALC gene (0.22%). Taken together, the variant was classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 2019 | 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; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 20886637, 23319190, 26795590, 27638593) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 03, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at