14-87947814-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_000153.4(GALC):c.1403C>G(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: 𝑓 0.0045 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 2 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.53

Publications

6 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

GALC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000153.4

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.

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 VariationId is 92495.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.1403C>G	p.Thr468Ser	missense_variant	Exon 13 of 17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 link	c.1403C>G	p.Thr468Ser	missense_variant	Exon 13 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes

AF:

0.00439

AC:

667

AN:

152050

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00110

AC:

273

AN:

248876

AF XY:

0.000763

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 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.:

Cov.:

AF XY:

0.000398

AC XY:

289

AN XY:

726648

show subpopulations

African (AFR)

AF:

0.0167

AC:

559

AN:

33392

American (AMR)

AF:

0.000672

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111110

Other (OTH)

AF:

0.00143

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00446

AC:

678

AN:

152168

Hom.:

Cov.:

AF XY:

0.00444

AC XY:

330

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0155

AC:

643

AN:

41546

American (AMR)

AF:

0.00170

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67972

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000726

Hom.:

Bravo

AF:

0.00518

ESP6500AA

AF:

0.0149

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.00133

AC:

161

Asia WGS

AF:

0.00231

AC:

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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.

Oct 31, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

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

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

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

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

T;T;T;T

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.8

M;.;.;.

PhyloP100

7.5

PrimateAI

Uncertain

0.50

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

Vest4

0.41

ClinPred

0.023

GERP RS

6.1

Varity_R

0.46

gMVP

0.83

Mutation Taster

=32/68

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over