rs111887056

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000153.4(GALC):c.61G>C(p.Ala21Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,586,544 control chromosomes in the GnomAD database, including 16,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 1112 hom., cov: 33)

Exomes 𝑓: 0.14 ( 15567 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.562

Publications

27 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 -19 ACMG points.

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=0.0018750429).

BP6

Variant 14-87993104-C-G is Benign according to our data. Variant chr14-87993104-C-G is described in ClinVar as Benign. ClinVar VariationId is 92508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.61G>C	p.Ala21Pro	missense_variant	Exon 1 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.61G>C	p.Ala21Pro	missense_variant	Exon 1 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

17026

AN:

152156

Hom.:

1109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0395

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0947

Gnomad FIN

AF:

0.154

Gnomad MID

AF:

0.134

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.115

AC:

21968

AN:

190848

AF XY:

0.114

show subpopulations

Gnomad AFR exome

AF:

0.0329

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.000725

Gnomad FIN exome

AF:

0.148

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.142

AC:

203924

AN:

1434276

Hom.:

15567

Cov.:

AF XY:

0.141

AC XY:

100074

AN XY:

710896

show subpopulations

African (AFR)

AF:

0.0341

AC:

1127

AN:

33054

American (AMR)

AF:

0.139

AC:

5735

AN:

41128

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

3008

AN:

25622

East Asian (EAS)

AF:

0.00124

AC:

AN:

38578

South Asian (SAS)

AF:

0.100

AC:

8314

AN:

82906

European-Finnish (FIN)

AF:

0.158

AC:

7762

AN:

49084

Middle Eastern (MID)

AF:

0.158

AC:

889

AN:

5614

European-Non Finnish (NFE)

AF:

0.154

AC:

169279

AN:

1099038

Other (OTH)

AF:

0.131

AC:

7762

AN:

59252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

9449

18898

28348

37797

47246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5930

11860

17790

23720

29650

<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:

0.112

AC:

17035

AN:

152268

Hom.:

1112

Cov.:

AF XY:

0.112

AC XY:

8361

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0396

AC:

1645

AN:

41566

American (AMR)

AF:

0.130

AC:

1994

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

414

AN:

3470

East Asian (EAS)

AF:

0.00232

AC:

AN:

5174

South Asian (SAS)

AF:

0.0946

AC:

457

AN:

4830

European-Finnish (FIN)

AF:

0.154

AC:

1638

AN:

10618

Middle Eastern (MID)

AF:

0.130

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.154

AC:

10488

AN:

67998

Other (OTH)

AF:

0.108

AC:

228

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

830

1660

2489

3319

4149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<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:

0.140

Hom.:

554

Bravo

AF:

0.106

TwinsUK

AF:

0.139

AC:

517

ALSPAC

AF:

0.146

AC:

564

ESP6500AA

AF:

0.0366

AC:

109

ESP6500EA

AF:

0.115

AC:

777

ExAC

AF:

0.0887

AC:

10059

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 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. -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Jan 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 26, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

0.56

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.020

N;N

REVEL

Uncertain

0.51

Sift

Benign

0.072

T;D

Sift4G

Benign

0.13

T;T

Polyphen

1.0

D;.

Vest4

0.17

MPC

0.66

ClinPred

0.033

GERP RS

3.2

PromoterAI

0.025

Neutral

(source)

Varity_R

0.14

gMVP

0.74

Mutation Taster

=96/4

polymorphism (auto)

(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