14-87941390-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000153.4(GALC):​c.1834+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,563,728 control chromosomes in the GnomAD database, including 767,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 69652 hom., cov: 27)
Exomes 𝑓: 0.99 ( 698149 hom. )

Consequence

GALC
NM_000153.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0002731
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.23
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
Variant 14-87941390-G-C is Benign according to our data. Variant chr14-87941390-G-C is described in ClinVar as [Benign]. Clinvar id is 92499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87941390-G-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GALCNM_000153.4 linkc.1834+5C>G splice_region_variant, intron_variant Intron 15 of 16 ENST00000261304.7 NP_000144.2 P54803-1A0A0A0MQV0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GALCENST00000261304.7 linkc.1834+5C>G splice_region_variant, intron_variant Intron 15 of 16 1 NM_000153.4 ENSP00000261304.2 P54803-1

Frequencies

GnomAD3 genomes
AF:
0.957
AC:
144818
AN:
151256
Hom.:
69616
Cov.:
27
show subpopulations
Gnomad AFR
AF:
0.862
Gnomad AMI
AF:
1.00
Gnomad AMR
AF:
0.984
Gnomad ASJ
AF:
0.998
Gnomad EAS
AF:
0.937
Gnomad SAS
AF:
0.994
Gnomad FIN
AF:
1.00
Gnomad MID
AF:
0.997
Gnomad NFE
AF:
0.999
Gnomad OTH
AF:
0.963
GnomAD3 exomes
AF:
0.984
AC:
226807
AN:
230474
Hom.:
111753
AF XY:
0.987
AC XY:
123264
AN XY:
124830
show subpopulations
Gnomad AFR exome
AF:
0.858
Gnomad AMR exome
AF:
0.992
Gnomad ASJ exome
AF:
0.998
Gnomad EAS exome
AF:
0.938
Gnomad SAS exome
AF:
0.997
Gnomad FIN exome
AF:
1.00
Gnomad NFE exome
AF:
0.999
Gnomad OTH exome
AF:
0.991
GnomAD4 exome
AF:
0.994
AC:
1403897
AN:
1412364
Hom.:
698149
Cov.:
27
AF XY:
0.995
AC XY:
700292
AN XY:
704036
show subpopulations
Gnomad4 AFR exome
AF:
0.852
Gnomad4 AMR exome
AF:
0.991
Gnomad4 ASJ exome
AF:
0.998
Gnomad4 EAS exome
AF:
0.953
Gnomad4 SAS exome
AF:
0.997
Gnomad4 FIN exome
AF:
1.00
Gnomad4 NFE exome
AF:
1.00
Gnomad4 OTH exome
AF:
0.986
GnomAD4 genome
AF:
0.957
AC:
144909
AN:
151364
Hom.:
69652
Cov.:
27
AF XY:
0.958
AC XY:
70778
AN XY:
73864
show subpopulations
Gnomad4 AFR
AF:
0.861
Gnomad4 AMR
AF:
0.984
Gnomad4 ASJ
AF:
0.998
Gnomad4 EAS
AF:
0.937
Gnomad4 SAS
AF:
0.995
Gnomad4 FIN
AF:
1.00
Gnomad4 NFE
AF:
0.999
Gnomad4 OTH
AF:
0.963
Alfa
AF:
0.975
Hom.:
22763
Bravo
AF:
0.951
Asia WGS
AF:
0.959
AC:
3330
AN:
3472
EpiCase
AF:
0.999
EpiControl
AF:
0.999

ClinVar

Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Benign:5
Nov 16, 2019
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:3
Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 19, 2015
Mayo Clinic Laboratories, Mayo Clinic
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

not specified Benign:2
Oct 27, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

GALC-related disorder Benign:1
Jul 21, 2021
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
BayesDel_noAF
Benign
-0.54
CADD
Benign
17
DANN
Benign
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00027
dbscSNV1_RF
Benign
0.14
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: rs448805; hg19: chr14-88407734; API