14-87933457-C-T

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.*1275G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 152,476 control chromosomes in the GnomAD database, including 17,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (17743 hom., cov: 32)
  • Exomes 𝑓: 0.50 (76 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.291

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=-0.86).
• BP6: Variant 14-87933457-C-T is Benign according to our data. Variant chr14-87933457-C-T is described in ClinVar as [Benign]. Clinvar id is 314731.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.*1275G>A		3_prime_UTR_variant	17/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.*1275G>A		3_prime_UTR_variant	17/17	1	NM_000153.4	P1
GALC	ENST00000555000.5	c.*74+442G>A		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.461 AC: 69883 AN: 151744 Hom.: 17742 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.473

GnomAD4 exome AF: 0.498 AC: 306 AN: 614 Hom.: 76 Cov.: 0 AF XY: 0.497 AC XY: 176 AN XY: 354

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.488

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.646

Gnomad4 OTH exome AF: 0.700

GnomAD4 genome AF: 0.460 AC: 69889 AN: 151862 Hom.: 17743 Cov.: 32 AF XY: 0.466 AC XY: 34579 AN XY: 74214

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.751

Gnomad4 SAS AF: 0.569

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.470

Alfa AF: 0.514 Hom.: 8098

Bravo AF: 0.456

Asia WGS AF: 0.560 AC: 1946 AN: 3476

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 12, 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	-0.86
Cadd	Benign	5.5
Dann	Benign	0.68

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: rs1042042; hg19: chr14-88399801;