14-87933279-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000153.4(GALC):c.*1453A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 152,306 control chromosomes in the GnomAD database, including 19,176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (19114 hom., cov: 32)
  • Exomes 𝑓: 0.53 (62 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.77

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-87933279-T-C is Benign according to our data. Variant chr14-87933279-T-C is described in ClinVar as [Benign]. Clinvar id is 314729.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.*1453A>G		3_prime_UTR_variant	17/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.*1453A>G		3_prime_UTR_variant	17/17	1	NM_000153.4	P1
GALC	ENST00000555000.5	c.*74+620A>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74744 AN: 151742 Hom.: 19084 Cov.: 32

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.485

GnomAD4 exome AF: 0.534 AC: 238 AN: 446 Hom.: 62 Cov.: 0 AF XY: 0.541 AC XY: 145 AN XY: 268

Gnomad4 AFR exome AF: 1.00

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.535

Gnomad4 NFE exome AF: 0.600

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.493 AC: 74827 AN: 151860 Hom.: 19114 Cov.: 32 AF XY: 0.488 AC XY: 36221 AN XY: 74230

Gnomad4 AFR AF: 0.603

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.491

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.425

Gnomad4 FIN AF: 0.476

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.490

Alfa AF: 0.470 Hom.: 17337

Bravo AF: 0.489

Asia WGS AF: 0.397 AC: 1381 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.17
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs405567; hg19: chr14-88399623; COSMIC: COSV54331851; COSMIC: COSV54331851;