14-87965554-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000153.4(GALC):c.984G>A(p.Gln328=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.68

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]

ACMG classification

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/exons	MANE	UniProt
GALC	NM_000153.4	c.984G>A	p.Gln328=	synonymous_variant	9/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.984G>A	p.Gln328=	synonymous_variant	9/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46761 AN: 151784 Hom.: 8463 Cov.: 32

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

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.: 35 AF XY: 0.366 AC XY: 265909 AN XY: 726546

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.: 32 AF XY: 0.314 AC XY: 23324 AN XY: 74230

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Other links and lift over

dbSNP: rs12888666; hg19: chr14-88431898; COSMIC: COSV54327408; COSMIC: COSV54327408;