Genetic Variant GALC:p.Gln328Gln (chr14-87965554-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000153.4(GALC):c.984G>A(p.Gln328Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,612,286 control chromosomes in the GnomAD database, including 108,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8463 hom., cov: 32)

Exomes 𝑓: 0.36 ( 100131 hom. )

Consequence

GALC
NM_000153.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.68

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 links:

LOC124903355 (HGNC:):

LOC124903355 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23).

BP6

Variant 14-87965554-C-T is Benign according to our data. Variant chr14-87965554-C-T is described in ClinVar as [Benign]. Clinvar id is 92513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965554-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.68 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.984G>A	p.Gln328Gln	synonymous_variant	Exon 9 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.984G>A	p.Gln328Gln	synonymous_variant	Exon 9 of 17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.308

AC:

46761

AN:

151784

Hom.:

8463

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.354

Gnomad AMR

AF:

0.438

Gnomad ASJ

AF:

0.370

Gnomad EAS

AF:

0.582

Gnomad SAS

AF:

0.413

Gnomad FIN

AF:

0.346

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.352

Gnomad OTH

AF:

0.326

GnomAD3 exomes

AF:

0.390

AC:

97013

AN:

248956

Hom.:

20479

AF XY:

0.392

AC XY:

52963

AN XY:

135050

show subpopulations

Gnomad AFR exome

AF:

0.116

Gnomad AMR exome

AF:

0.519

Gnomad ASJ exome

AF:

0.380

Gnomad EAS exome

AF:

0.596

Gnomad SAS exome

AF:

0.426

Gnomad FIN exome

AF:

0.338

Gnomad NFE exome

AF:

0.356

Gnomad OTH exome

AF:

0.384

GnomAD4 exome

AF:

0.364

AC:

531419

AN:

1460384

Hom.:

100131

Cov.:

AF XY:

0.366

AC XY:

265909

AN XY:

726546

show subpopulations

Gnomad4 AFR exome

AF:

0.113

Gnomad4 AMR exome

AF:

0.507

Gnomad4 ASJ exome

AF:

0.378

Gnomad4 EAS exome

AF:

0.612

Gnomad4 SAS exome

AF:

0.429

Gnomad4 FIN exome

AF:

0.343

Gnomad4 NFE exome

AF:

0.353

Gnomad4 OTH exome

AF:

0.361

GnomAD4 genome

AF:

0.308

AC:

46763

AN:

151902

Hom.:

8463

Cov.:

AF XY:

0.314

AC XY:

23324

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.125

Gnomad4 AMR

AF:

0.438

Gnomad4 ASJ

AF:

0.370

Gnomad4 EAS

AF:

0.582

Gnomad4 SAS

AF:

0.413

Gnomad4 FIN

AF:

0.346

Gnomad4 NFE

AF:

0.352

Gnomad4 OTH

AF:

0.324

Alfa

AF:

0.351

Hom.:

15648

Bravo

AF:

0.310

Asia WGS

AF:

0.408

AC:

1420

AN:

3478

EpiCase

AF:

0.367

EpiControl

AF:

0.371

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign:5

Nov 19, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:4

Apr 03, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2015

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

-0.23

CADD

Benign

6.8

DANN

Benign

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over