14-87947814-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000153.4(GALC):ā€‹c.1403C>Gā€‹(p.Thr468Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000845 in 1,612,742 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0045 ( 4 hom., cov: 32)
Exomes š‘“: 0.00047 ( 2 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

5
8
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 7.53
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0118046105).
BP6
Variant 14-87947814-G-C is Benign according to our data. Variant chr14-87947814-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92495.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00446 (678/152168) while in subpopulation AFR AF= 0.0155 (643/41546). AF 95% confidence interval is 0.0145. There are 4 homozygotes in gnomad4. There are 330 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GALCNM_000153.4 linkc.1403C>G p.Thr468Ser missense_variant Exon 13 of 17 ENST00000261304.7 NP_000144.2 P54803-1A0A0A0MQV0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GALCENST00000261304.7 linkc.1403C>G p.Thr468Ser missense_variant Exon 13 of 17 1 NM_000153.4 ENSP00000261304.2 P54803-1

Frequencies

GnomAD3 genomes
AF:
0.00439
AC:
667
AN:
152050
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0153
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00171
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00383
GnomAD3 exomes
AF:
0.00110
AC:
273
AN:
248876
Hom.:
1
AF XY:
0.000763
AC XY:
103
AN XY:
135014
show subpopulations
Gnomad AFR exome
AF:
0.0162
Gnomad AMR exome
AF:
0.000494
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.000497
GnomAD4 exome
AF:
0.000469
AC:
685
AN:
1460574
Hom.:
2
Cov.:
31
AF XY:
0.000398
AC XY:
289
AN XY:
726648
show subpopulations
Gnomad4 AFR exome
AF:
0.0167
Gnomad4 AMR exome
AF:
0.000672
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00143
GnomAD4 genome
AF:
0.00446
AC:
678
AN:
152168
Hom.:
4
Cov.:
32
AF XY:
0.00444
AC XY:
330
AN XY:
74404
show subpopulations
Gnomad4 AFR
AF:
0.0155
Gnomad4 AMR
AF:
0.00170
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00379
Alfa
AF:
0.000726
Hom.:
0
Bravo
AF:
0.00518
ESP6500AA
AF:
0.0149
AC:
63
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.00133
AC:
161
Asia WGS
AF:
0.00231
AC:
8
AN:
3476
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Uncertain:1Benign:3
Oct 31, 2019
Natera, Inc.
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 31, 2018
SIB Swiss Institute of Bioinformatics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Krabbe disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. BS1 => Allele frequency is greater than expected for disorder. BS2-Supporting => BS2 downgraded in strength to supporting. -

not provided Benign:3
Nov 30, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 25, 2021
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32019516, 27638593, 9338580, 21228398, 20981092, 22995991) -

Apr 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

GALC: BS1 -

not specified Benign:1
Mar 14, 2013
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

GALC-related disorder Benign:1
Apr 12, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.084
T
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.;.;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.73
T;T;T;T
MetaRNN
Benign
0.012
T;T;T;T
MetaSVM
Uncertain
0.66
D
MutationAssessor
Uncertain
2.8
M;.;.;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-3.8
D;D;D;D
REVEL
Pathogenic
0.72
Sift
Uncertain
0.010
D;D;D;D
Sift4G
Uncertain
0.016
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.41
MutPred
0.72
Gain of catalytic residue at T468 (P = 0.0016);.;.;.;
MVP
0.98
MPC
0.56
ClinPred
0.023
T
GERP RS
6.1
Varity_R
0.46
gMVP
0.83

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34134328; hg19: chr14-88414158; COSMIC: COSV99039387; COSMIC: COSV99039387; API