14-87933144-A-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.*1588T>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 0.46 in 152,014 control chromosomes in the GnomAD database, including 17,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (17725 hom., cov: 32)
  • Exomes 𝑓: 0.51 (15 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08

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=-0.74).
• BP6: Variant 14-87933144-A-C is Benign according to our data. Variant chr14-87933144-A-C is described in ClinVar as [Benign]. Clinvar id is 314727.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.*1588T>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.*1588T>G		3_prime_UTR_variant	17/17	1	NM_000153.4	P1
GALC	ENST00000555000.5	c.*74+755T>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69842 AN: 151794 Hom.: 17724 Cov.: 32

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.472

GnomAD4 exome AF: 0.510 AC: 52 AN: 102 Hom.: 15 Cov.: 0 AF XY: 0.500 AC XY: 36 AN XY: 72

Gnomad4 FIN exome AF: 0.489

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.460 AC: 69848 AN: 151912 Hom.: 17725 Cov.: 32 AF XY: 0.466 AC XY: 34569 AN XY: 74246

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.585

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.750

Gnomad4 SAS AF: 0.570

Gnomad4 FIN AF: 0.525

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.469

Alfa AF: 0.522 Hom.: 30354

Bravo AF: 0.456

Asia WGS AF: 0.559 AC: 1947 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 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	-0.74
Cadd	Benign	5.1
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs17198; hg19: chr14-88399488; COSMIC: COSV54328309; COSMIC: COSV54328309;