rs12432149

Positions:

• chr14-87941573-G-A
• chr14-87941573-G-C
• chr14-87941573-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000261304.7(GALC):​c.1671-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,498,288 control chromosomes in the GnomAD database, including 210,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17740 hom., cov: 32)
  • Exomes 𝑓: 0.53 (192280 hom.)
• Consequence: GALC ENST00000261304.7 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.03

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-87941573-G-A is Benign according to our data. Variant chr14-87941573-G-A is described in ClinVar as [Benign]. Clinvar id is 92496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87941573-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4	c.1671-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.1671-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000153.4	ENSP00000261304	P1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69840 AN: 151698 Hom.: 17739 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.472

GnomAD3 exomes AF: 0.551 AC: 136630 AN: 248100 Hom.: 39307 AF XY: 0.552 AC XY: 74351 AN XY: 134636

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.675

Gnomad ASJ exome AF: 0.513

Gnomad EAS exome AF: 0.764

Gnomad SAS exome AF: 0.577

Gnomad FIN exome AF: 0.521

Gnomad NFE exome AF: 0.525

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.529 AC: 712053 AN: 1346472 Hom.: 192280 Cov.: 23 AF XY: 0.531 AC XY: 358949 AN XY: 676576

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.664

Gnomad4 ASJ exome AF: 0.514

Gnomad4 EAS exome AF: 0.757

Gnomad4 SAS exome AF: 0.579

Gnomad4 FIN exome AF: 0.530

Gnomad4 NFE exome AF: 0.520

Gnomad4 OTH exome AF: 0.528

GnomAD4 genome AF: 0.460 AC: 69846 AN: 151816 Hom.: 17740 Cov.: 32 AF XY: 0.466 AC XY: 34566 AN XY: 74210

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.751

Gnomad4 SAS AF: 0.570

Gnomad4 FIN AF: 0.525

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.468

Alfa AF: 0.492 Hom.: 3781

Bravo AF: 0.456

Asia WGS AF: 0.560 AC: 1948 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

Galactosylceramide beta-galactosidase deficiency Benign:4

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. -
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	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.90
CADD	Benign	0.024
DANN	Benign	0.26

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: rs12432149; hg19: chr14-88407917;