rs398076

chr14-87947867-G-A

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.1350C>T(p.Ser450=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,610,008 control chromosomes in the GnomAD database, including 126,114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12159 hom., cov: 31)
  • Exomes 𝑓: 0.39 (113955 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.109

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=-0.79).
• BP6: Variant 14-87947867-G-A is Benign according to our data. Variant chr14-87947867-G-A is described in ClinVar as [Benign]. Clinvar id is 92494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87947867-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.109 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.1350C>T	p.Ser450=	synonymous_variant	13/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.1350C>T	p.Ser450=	synonymous_variant	13/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60115 AN: 151636 Hom.: 12146 Cov.: 31

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.395

GnomAD3 exomes AF: 0.368 AC: 91227 AN: 248096 Hom.: 17396 AF XY: 0.372 AC XY: 50061 AN XY: 134614

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.174

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.392 AC: 571804 AN: 1458254 Hom.: 113955 Cov.: 35 AF XY: 0.393 AC XY: 284890 AN XY: 725544

Gnomad4 AFR exome AF: 0.435

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.194

Gnomad4 SAS exome AF: 0.385

Gnomad4 FIN exome AF: 0.399

Gnomad4 NFE exome AF: 0.402

Gnomad4 OTH exome AF: 0.386

GnomAD4 genome AF: 0.396 AC: 60162 AN: 151754 Hom.: 12159 Cov.: 31 AF XY: 0.394 AC XY: 29204 AN XY: 74144

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.400

Gnomad4 OTH AF: 0.401

Alfa AF: 0.394 Hom.: 23585

Bravo AF: 0.390

Asia WGS AF: 0.369 AC: 1283 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.384

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	Genome-Nilou Lab	Jul 01, 2021	- -
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, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 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	-0.79
Cadd	Benign	2.4
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs398076; hg19: chr14-88414211; COSMIC: COSV54324856; COSMIC: COSV54324856;