Genetic Variant GALC:p.Ser303Phe (chr14-87968335-G-A) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000153.4(GALC):c.908C>T(p.Ser303Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,606,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

GALC
NM_000153.4 missense, splice_region

Scores

Splicing: ADA: 0.9533

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 9.88

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: Laboratory for Molecular Medicine, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

GALC links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000153.4

PM2

Very rare variant in population databases, with high coverage;

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, 0.946

PP5

Variant 14-87968335-G-A is Pathogenic according to our data. Variant chr14-87968335-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280957.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	UniProt
GALC	NM_000153.4	MANE Select	c.908C>T	p.Ser303Phe	missense splice_region	Exon 8 of 17	NP_000144.2	P54803-1
GALC	NM_001201401.2		c.839C>T	p.Ser280Phe	missense splice_region	Exon 7 of 16	NP_001188330.1	P54803-3
GALC	NM_001201402.2		c.830C>T	p.Ser277Phe	missense splice_region	Exon 8 of 17	NP_001188331.1	P54803-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GALC	ENST00000261304.7	TSL:1 MANE Select	c.908C>T	p.Ser303Phe	missense splice_region	Exon 8 of 17	ENSP00000261304.2	P54803-1
GALC	ENST00000622264.4	TSL:1	c.896C>T	p.Ser299Phe	missense splice_region	Exon 8 of 10	ENSP00000480649.1	A0A087WX10
GALC	ENST00000474294.6	TSL:1	n.898C>T		splice_region non_coding_transcript_exon	Exon 8 of 10

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000244

AC:

AN:

245686

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1454544

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

723694

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33042

American (AMR)

AF:

0.00

AC:

AN:

43598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25806

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85218

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

1108224

Other (OTH)

AF:

0.00

AC:

AN:

59990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

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:

0.00000659

AC:

AN:

151766

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74096

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41296

American (AMR)

AF:

0.00

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2078

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

Alfa

AF:

0.0000338

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000414

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Galactosylceramide beta-galactosidase deficiency (9)

not provided (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

PhyloP100

9.9

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.86

MutPred

0.79

Gain of catalytic residue at A306 (P = 5e-04)

MVP

0.99

MPC

0.61

ClinPred

0.92

GERP RS

4.7

Varity_R

0.72

gMVP

0.92

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Pathogenic

0.75

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over