rs367327

chr14-87945603-T-C

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.1620A>G(p.Thr540=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,609,970 control chromosomes in the GnomAD database, including 791,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70143 hom., cov: 31)
  • Exomes 𝑓: 0.99 (720877 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.81

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=-0.93).
• BP6: Variant 14-87945603-T-C is Benign according to our data. Variant chr14-87945603-T-C is described in ClinVar as [Benign]. Clinvar id is 167118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87945603-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.1620A>G	p.Thr540=	synonymous_variant	14/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.1620A>G	p.Thr540=	synonymous_variant	14/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.959 AC: 145664 AN: 151938 Hom.: 70104 Cov.: 31

Gnomad AFR AF: 0.866

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.994

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.964

GnomAD3 exomes AF: 0.985 AC: 245232 AN: 248934 Hom.: 120938 AF XY: 0.988 AC XY: 133465 AN XY: 135054

Gnomad AFR exome AF: 0.863

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 0.939

Gnomad SAS exome AF: 0.997

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.994 AC: 1449420 AN: 1457914 Hom.: 720877 Cov.: 39 AF XY: 0.995 AC XY: 721779 AN XY: 725526

Gnomad4 AFR exome AF: 0.859

Gnomad4 AMR exome AF: 0.991

Gnomad4 ASJ exome AF: 0.998

Gnomad4 EAS exome AF: 0.953

Gnomad4 SAS exome AF: 0.997

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.986

GnomAD4 genome AF: 0.959 AC: 145763 AN: 152056 Hom.: 70143 Cov.: 31 AF XY: 0.960 AC XY: 71334 AN XY: 74332

Gnomad4 AFR AF: 0.866

Gnomad4 AMR AF: 0.984

Gnomad4 ASJ AF: 0.998

Gnomad4 EAS AF: 0.938

Gnomad4 SAS AF: 0.995

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.965

Alfa AF: 0.989 Hom.: 82896

Bravo AF: 0.952

Asia WGS AF: 0.961 AC: 3342 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Galactosylceramide beta-galactosidase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.36
Dann	Benign	0.30

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: rs367327; hg19: chr14-88411947;