rs112992946

Positions:

• chr14-87993123-C-G
• chr14-87993123-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000153.4(GALC):​c.42G>C​(p.Ala14=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,586,138 control chromosomes in the GnomAD database, including 16,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1114 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15584 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0380

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 14-87993123-C-G is Benign according to our data. Variant chr14-87993123-C-G is described in ClinVar as [Benign]. Clinvar id is 92505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87993123-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.038 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4	c.42G>C	p.Ala14=	synonymous_variant	1/17	ENST00000261304.7	NP_000144.2
GALC	NM_001201401.2	c.42G>C	p.Ala14=	synonymous_variant	1/16		NP_001188330.1
GALC	NM_001201402.2	c.117+260G>C		intron_variant			NP_001188331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.42G>C	p.Ala14=	synonymous_variant	1/17	1	NM_000153.4	ENSP00000261304	P1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17033 AN: 152168 Hom.: 1111 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0945

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.109

GnomAD3 exomes AF: 0.117 AC: 22335 AN: 190218 Hom.: 1544 AF XY: 0.116 AC XY: 12174 AN XY: 104588

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.000810

Gnomad SAS exome AF: 0.0956

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.142 AC: 204126 AN: 1433858 Hom.: 15584 Cov.: 33 AF XY: 0.141 AC XY: 100162 AN XY: 710602

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.00125

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.112 AC: 17042 AN: 152280 Hom.: 1114 Cov.: 33 AF XY: 0.112 AC XY: 8368 AN XY: 74462

Gnomad4 AFR AF: 0.0396

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0944

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.108

Alfa AF: 0.118 Hom.: 448

Bravo AF: 0.106

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

Galactosylceramide beta-galactosidase deficiency Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.1
DANN	Benign	0.73

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: rs112992946; hg19: chr14-88459467;