GeneBe

rs11623

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000153.4(GALC):​c.169G>T​(p.Gly57Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G57R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

GALC
NM_000153.4 missense

Scores

12
6

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.91

Publications

9 publications found
Variant links:
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 disease
    Inheritance: 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 13 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000153.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-87992996-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1324445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.949
PP5
Variant 14-87992996-C-A is Pathogenic according to our data. Variant chr14-87992996-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1346242.Status of the report is criteria_provided_single_submitter, 1 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

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GALC
NM_000153.4
MANE Select
c.169G>Tp.Gly57Cys
missense
Exon 1 of 17NP_000144.2
GALC
NM_001424072.1
c.-102G>T
5_prime_UTR_premature_start_codon_gain
Exon 1 of 18NP_001411001.1
GALC
NM_001424075.1
c.-268G>T
5_prime_UTR_premature_start_codon_gain
Exon 1 of 18NP_001411004.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GALC
ENST00000261304.7
TSL:1 MANE Select
c.169G>Tp.Gly57Cys
missense
Exon 1 of 17ENSP00000261304.2
GALC
ENST00000622264.4
TSL:1
c.157G>Tp.Gly53Cys
missense
Exon 1 of 10ENSP00000480649.1
GALC
ENST00000474294.6
TSL:1
n.159G>T
non_coding_transcript_exon
Exon 1 of 10

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
137710
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1382936
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
684312
African (AFR)
AF:
0.00
AC:
0
AN:
28544
American (AMR)
AF:
0.00
AC:
0
AN:
37248
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24340
East Asian (EAS)
AF:
0.00
AC:
0
AN:
33536
South Asian (SAS)
AF:
0.00
AC:
0
AN:
78514
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
37834
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4108
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1081556
Other (OTH)
AF:
0.00
AC:
0
AN:
57256
GnomAD4 genome
Cov.:
33

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
1
-
-
Galactosylceramide beta-galactosidase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.0
M
PhyloP100
6.9
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-7.2
D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.75
Gain of catalytic residue at S62 (P = 0)
MVP
0.99
MPC
0.60
ClinPred
1.0
D
GERP RS
3.2
PromoterAI
-0.030
Neutral
Varity_R
0.90
gMVP
0.98
Mutation Taster
=21/79
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs11623; hg19: chr14-88459340; API