14-87986601-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000153.4(GALC):c.330C>T(p.Asp110Asp) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.04 in 1,602,176 control chromosomes in the GnomAD database, including 1,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 126 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1423 hom. )

Consequence

GALC
NM_000153.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00003664

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.75

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 14-87986601-G-A is Benign according to our data. Variant chr14-87986601-G-A is described in ClinVar as Benign. ClinVar VariationId is 92502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.031 (4712/152096) while in subpopulation NFE AF = 0.0465 (3162/67992). AF 95% confidence interval is 0.0452. There are 126 homozygotes in GnomAd4. There are 2282 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 126 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.330C>T	p.Asp110Asp	splice_region_variant, synonymous_variant	Exon 4 of 17	ENST00000261304.7	NP_000144.2	P54803-1A0A0A0MQV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 link	c.330C>T	p.Asp110Asp	splice_region_variant, synonymous_variant	Exon 4 of 17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.0310

AC:

4711

AN:

151978

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00846

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0490

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.0501

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.0345

GnomAD2 exomes

AF:

0.0331

AC:

8216

AN:

248540

AF XY:

0.0340

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0493

Gnomad EAS exome

AF:

0.00117

Gnomad FIN exome

AF:

0.0565

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0309

GnomAD4 exome

AF:

0.0410

AC:

59415

AN:

1450080

Hom.:

1423

Cov.:

AF XY:

0.0408

AC XY:

29482

AN XY:

722150

show subpopulations

African (AFR)

AF:

0.00518

AC:

172

AN:

33204

American (AMR)

AF:

0.0170

AC:

757

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0500

AC:

1304

AN:

26064

East Asian (EAS)

AF:

0.000277

AC:

AN:

39646

South Asian (SAS)

AF:

0.0213

AC:

1831

AN:

85970

European-Finnish (FIN)

AF:

0.0528

AC:

2817

AN:

53328

Middle Eastern (MID)

AF:

0.0153

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0458

AC:

50430

AN:

1101468

Other (OTH)

AF:

0.0334

AC:

2005

AN:

59998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

2626

5252

7877

10503

13129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1838

3676

5514

7352

9190

<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:

0.0310

AC:

4712

AN:

152096

Hom.:

126

Cov.:

AF XY:

0.0307

AC XY:

2282

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00844

AC:

350

AN:

41492

American (AMR)

AF:

0.0183

AC:

279

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0490

AC:

170

AN:

3470

East Asian (EAS)

AF:

0.000775

AC:

AN:

5162

South Asian (SAS)

AF:

0.0191

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0501

AC:

530

AN:

10574

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0465

AC:

3162

AN:

67992

Other (OTH)

AF:

0.0337

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

218

437

655

874

1092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0405

Hom.:

488

Bravo

AF:

0.0284

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0465

EpiControl

AF:

0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign:5

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Jan 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

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

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.56

PhyloP100

3.8

Mutation Taster

=51/49

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000037

dbscSNV1_RF

Benign

0.11

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