Genetic Variant GALC:c.329-35G>A (chr14-87986637-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000153.4(GALC):c.329-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,314,266 control chromosomes in the GnomAD database, including 13,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1139 hom., cov: 31)

Exomes 𝑓: 0.14 ( 12723 hom. )

Consequence

GALC
NM_000153.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.131

Publications

11 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 14-87986637-C-T is Benign according to our data. Variant chr14-87986637-C-T is described in ClinVar as Benign. ClinVar VariationId is 255375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
GALC	NM_000153.4	MANE Select	c.329-35G>A	intron	N/A	NP_000144.2	P54803-1
GALC	NM_001201401.2		c.260-35G>A	intron	N/A	NP_001188330.1	P54803-3
GALC	NM_001201402.2		c.251-35G>A	intron	N/A	NP_001188331.1	P54803-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GALC	ENST00000261304.7	TSL:1 MANE Select	c.329-35G>A	intron	N/A	ENSP00000261304.2	P54803-1
GALC	ENST00000622264.4	TSL:1	c.317-35G>A	intron	N/A	ENSP00000480649.1	A0A087WX10
GALC	ENST00000474294.6	TSL:1	n.319-35G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17102

AN:

151750

Hom.:

1136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0398

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.0954

Gnomad FIN

AF:

0.154

Gnomad MID

AF:

0.125

Gnomad NFE

AF:

0.156

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.127

AC:

30189

AN:

237698

AF XY:

0.127

show subpopulations

Gnomad AFR exome

AF:

0.0377

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.116

Gnomad EAS exome

AF:

0.00247

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.156

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.142

AC:

164569

AN:

1162398

Hom.:

12723

Cov.:

AF XY:

0.140

AC XY:

83213

AN XY:

592304

show subpopulations

African (AFR)

AF:

0.0362

AC:

991

AN:

27378

American (AMR)

AF:

0.146

AC:

6361

AN:

43532

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

2842

AN:

24238

East Asian (EAS)

AF:

0.00170

AC:

AN:

38308

South Asian (SAS)

AF:

0.102

AC:

8129

AN:

79612

European-Finnish (FIN)

AF:

0.162

AC:

8529

AN:

52576

Middle Eastern (MID)

AF:

0.163

AC:

842

AN:

5160

European-Non Finnish (NFE)

AF:

0.155

AC:

130155

AN:

841114

Other (OTH)

AF:

0.132

AC:

6655

AN:

50480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

6841

13683

20524

27366

34207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3912

7824

11736

15648

19560

<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:

0.113

AC:

17111

AN:

151868

Hom.:

1139

Cov.:

AF XY:

0.113

AC XY:

8377

AN XY:

74184

show subpopulations

African (AFR)

AF:

0.0398

AC:

1651

AN:

41460

American (AMR)

AF:

0.129

AC:

1965

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

414

AN:

3470

East Asian (EAS)

AF:

0.00233

AC:

AN:

5154

South Asian (SAS)

AF:

0.0953

AC:

459

AN:

4818

European-Finnish (FIN)

AF:

0.154

AC:

1614

AN:

10502

Middle Eastern (MID)

AF:

0.121

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.156

AC:

10605

AN:

67946

Other (OTH)

AF:

0.108

AC:

228

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

714

1428

2142

2856

3570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.134

Hom.:

308

Bravo

AF:

0.107

Asia WGS

AF:

0.0550

AC:

192

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Galactosylceramide beta-galactosidase deficiency (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

0.13

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over