14-87933606-C-T

Position:

• chr14-87933606-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.*1126G>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 0.115 in 178,520 control chromosomes in the GnomAD database, including 1,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1141 hom., cov: 33)
  • Exomes 𝑓: 0.14 (304 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16

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]

GALC (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-87933606-C-T is Benign according to our data. Variant chr14-87933606-C-T is described in ClinVar as [Benign]. Clinvar id is 314733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4	c.*1126G>A		3_prime_UTR_variant	17/17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304	c.*1126G>A		3_prime_UTR_variant	17/17	1	NM_000153.4	ENSP00000261304.2
GALC	ENST00000555000.5	n.*74+293G>A		intron_variant		2		ENSP00000450472.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16717 AN: 151996 Hom.: 1139 Cov.: 33

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0955

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.142 AC: 3743 AN: 26404 Hom.: 304 Cov.: 0 AF XY: 0.147 AC XY: 1950 AN XY: 13270

Gnomad4 AFR exome AF: 0.0374

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.00583

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.166

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.110 AC: 16717 AN: 152116 Hom.: 1141 Cov.: 33 AF XY: 0.110 AC XY: 8158 AN XY: 74342

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0949

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.108

Alfa AF: 0.145 Hom.: 393

Bravo AF: 0.102

Asia WGS AF: 0.0560 AC: 195 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.65

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: rs1042035; hg19: chr14-88399950;