rs9672064

chr14-87945591-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000153.4(GALC):c.1632T>C(p.Asp544=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,609,838 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.149

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 14-87945591-A-G is Benign according to our data. Variant chr14-87945591-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 495671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87945591-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.149 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.1632T>C	p.Asp544=	synonymous_variant	14/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.1632T>C	p.Asp544=	synonymous_variant	14/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 273 AN: 152040 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000462 AC: 115 AN: 248928 Hom.: 0 AF XY: 0.000326 AC XY: 44 AN XY: 135056

Gnomad AFR exome AF: 0.00660

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000153 AC: 223 AN: 1457680 Hom.: 2 Cov.: 30 AF XY: 0.000116 AC XY: 84 AN XY: 725440

Gnomad4 AFR exome AF: 0.00576

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.00179 AC: 272 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74392

Gnomad4 AFR AF: 0.00645

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00188

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2016	Variant summary: The c.1632C>T (p.Asp544=) in GALC gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in control population dataset of ExAC at a frequency of 0.00058 (70/120542 chrs tested), predominantly in individuals of African descent (0.0066; 64/9800 chrs tested). The latter freuency exceeds the estimated maximal expected allele frequency of a pathogenic variant in GALC gene (0.0022). The variant has been reported in an individual with biochemically confirmed Krabble disease who was homozygous for p.G553R a known pathogenic variant and, therefore, p.Asp544= was considered to be a neutral polymorphism. Taking together, the variant was classified as Likely Benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Galactosylceramide beta-galactosidase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.40
Dann	Benign	0.40

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: rs9672064; hg19: chr14-88411935;