NM_000153.4:c.433dupA
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000153.4(GALC):c.433dupA(p.Thr145AsnfsTer43) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000281 in 1,425,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T145T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
GALC
NM_000153.4 frameshift
NM_000153.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.23
Publications
0 publications found
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]
GALC Gene-Disease associations (from GenCC):
- Krabbe diseaseInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp
Genome browser will be placed here
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 14-87986497-G-GT is Pathogenic according to our data. Variant chr14-87986497-G-GT is described in ClinVar as Pathogenic. ClinVar VariationId is 553285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000153.4. 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 |
|---|---|---|---|---|---|---|---|---|---|
| GALC | NM_000153.4 | MANE Select | c.433dupA | p.Thr145AsnfsTer43 | frameshift | Exon 4 of 17 | NP_000144.2 | ||
| GALC | NM_001201401.2 | c.364dupA | p.Thr122AsnfsTer43 | frameshift | Exon 3 of 16 | NP_001188330.1 | |||
| GALC | NM_001201402.2 | c.355dupA | p.Thr119AsnfsTer43 | frameshift | Exon 4 of 17 | NP_001188331.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GALC | ENST00000261304.7 | TSL:1 MANE Select | c.433dupA | p.Thr145AsnfsTer43 | frameshift | Exon 4 of 17 | ENSP00000261304.2 | ||
| GALC | ENST00000622264.4 | TSL:1 | c.421dupA | p.Thr141fs | frameshift | Exon 4 of 10 | ENSP00000480649.1 | ||
| GALC | ENST00000474294.6 | TSL:1 | n.423dupA | non_coding_transcript_exon | Exon 4 of 10 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000281 AC: 4AN: 1425992Hom.: 0 Cov.: 27 AF XY: 0.00000281 AC XY: 2AN XY: 711584 show subpopulations
GnomAD4 exome
AF:
AC:
4
AN:
1425992
Hom.:
Cov.:
27
AF XY:
AC XY:
2
AN XY:
711584
show subpopulations
African (AFR)
AF:
AC:
0
AN:
32716
American (AMR)
AF:
AC:
0
AN:
44656
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25914
East Asian (EAS)
AF:
AC:
0
AN:
39510
South Asian (SAS)
AF:
AC:
0
AN:
85528
European-Finnish (FIN)
AF:
AC:
0
AN:
53320
Middle Eastern (MID)
AF:
AC:
0
AN:
5690
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1079510
Other (OTH)
AF:
AC:
0
AN:
59148
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
4
-
-
Galactosylceramide beta-galactosidase deficiency (4)
1
-
-
not provided (1)
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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