Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000153.4(GALC):c.169G>A(p.Gly57Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000013 in 1,534,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O: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

GALC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 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, 0.955

PP5

Variant 14-87992996-C-T is Pathogenic according to our data. Variant chr14-87992996-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 193054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALC	NM_000153.4	MANE Select	c.169G>A	p.Gly57Ser	missense	Exon 1 of 17	NP_000144.2
GALC	NM_001201401.2		c.169G>A	p.Gly57Ser	missense	Exon 1 of 16	NP_001188330.1
GALC	NR_187582.1		n.187G>A		non_coding_transcript_exon	Exon 1 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALC	ENST00000261304.7	TSL:1 MANE Select	c.169G>A	p.Gly57Ser	missense	Exon 1 of 17	ENSP00000261304.2
GALC	ENST00000622264.4	TSL:1	c.157G>A	p.Gly53Ser	missense	Exon 1 of 10	ENSP00000480649.1
GALC	ENST00000474294.6	TSL:1	n.159G>A		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1382938

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28544

American (AMR)

AF:

0.00

AC:

AN:

37248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24340

East Asian (EAS)

AF:

0.00

AC:

AN:

33536

South Asian (SAS)

AF:

0.00

AC:

AN:

78516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1081556

Other (OTH)

AF:

0.00

AC:

AN:

57256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Galactosylceramide beta-galactosidase deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.3

PhyloP100

6.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.97

MutPred

0.79

Gain of catalytic residue at S62 (P = 2e-04)

MVP

1.0

MPC

0.53

ClinPred

1.0

GERP RS

3.2

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.73

gMVP

0.96

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over