14-87986582-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 25 ACMG points: 25P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000153.4(GALC):c.349A>C(p.Met117Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,080 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M117V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.99

Publications

13 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 25 ACMG points.

PS1

Transcript NM_000153.4 (GALC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr14-87986582-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92504.

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, 0.856

PP5

Variant 14-87986582-T-G is Pathogenic according to our data. Variant chr14-87986582-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1066196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.349A>C	p.Met117Leu	missense_variant	Exon 4 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.349A>C	p.Met117Leu	missense_variant	Exon 4 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152106

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:

0.00000137

AC:

AN:

1460974

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111208

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Pathogenic:1

Mar 25, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine with leucine at codon 117 of the GALC protein (p.Met117Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Krabbe disease (PMID: 8940268). This missense change is also known in the literature as p.Met101Leu. This variant has been reported to affect GALC protein function (PMID: 8940268). This variant disrupts the p.Met117 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23430802, 30089515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:1

Apr 12, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM2, PM5, PS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.88

D;.;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.1

M;.;.;.

PhyloP100

8.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.5

D;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.018

D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.81

MutPred

0.76

Gain of catalytic residue at E113 (P = 0.002);.;.;.;

MVP

0.88

MPC

0.57

ClinPred

0.97

GERP RS

5.4

Varity_R

0.53

gMVP

0.88

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over