rs185943390

Positions:

• chr14-87993491-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001201402.2(GALC):​c.9G>T​(p.Gly3=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,535,102 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G3G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: GALC NM_001201402.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.259

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-87993491-C-A is Benign according to our data. Variant chr14-87993491-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374669.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr14-87993491-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.259 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_001201402.2	c.9G>T	p.Gly3=	synonymous_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000393569.6	c.9G>T	p.Gly3=	synonymous_variant	1/17	2

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152190 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00130 AC: 170 AN: 130812 Hom.: 0 AF XY: 0.00133 AC XY: 95 AN XY: 71392

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.000864

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00156

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00146 AC: 2025 AN: 1382794 Hom.: 3 Cov.: 31 AF XY: 0.00158 AC XY: 1075 AN XY: 682338

Gnomad4 AFR exome AF: 0.0000950

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.000675

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.00160

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.00119 AC: 182 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74472

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00152

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	GALC: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.73

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs185943390; hg19: chr14-88459835;