14-87934023-T-G

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.*709A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0729 in 1,534,004 control chromosomes in the GnomAD database, including 4,644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (318 hom., cov: 33)
  • Exomes 𝑓: 0.075 (4326 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00700

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=-0.81).
• BP6: Variant 14-87934023-T-G is Benign according to our data. Variant chr14-87934023-T-G is described in ClinVar as [Benign]. Clinvar id is 314737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.*709A>C		3_prime_UTR_variant	17/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.*709A>C		3_prime_UTR_variant	17/17	1	NM_000153.4	P1
GALC	ENST00000544807.6	c.1744-24A>C		intron_variant		2
GALC	ENST00000555000.5	c.1279-24A>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7911 AN: 152056 Hom.: 318 Cov.: 33

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.0799

Gnomad EAS AF: 0.000968

Gnomad SAS AF: 0.0489

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0807

Gnomad OTH AF: 0.0478

GnomAD3 exomes AF: 0.0571 AC: 7472 AN: 130826 Hom.: 284 AF XY: 0.0596 AC XY: 4259 AN XY: 71412

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.0771

Gnomad EAS exome AF: 0.000661

Gnomad SAS exome AF: 0.0518

Gnomad FIN exome AF: 0.0339

Gnomad NFE exome AF: 0.0839

Gnomad OTH exome AF: 0.0770

GnomAD4 exome AF: 0.0752 AC: 103961 AN: 1381830 Hom.: 4326 Cov.: 32 AF XY: 0.0748 AC XY: 51021 AN XY: 681878

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.0402

Gnomad4 ASJ exome AF: 0.0738

Gnomad4 EAS exome AF: 0.000390

Gnomad4 SAS exome AF: 0.0513

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0841

Gnomad4 OTH exome AF: 0.0686

GnomAD4 genome AF: 0.0520 AC: 7910 AN: 152174 Hom.: 318 Cov.: 33 AF XY: 0.0489 AC XY: 3638 AN XY: 74386

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.0471

Gnomad4 ASJ AF: 0.0799

Gnomad4 EAS AF: 0.000970

Gnomad4 SAS AF: 0.0491

Gnomad4 FIN AF: 0.0277

Gnomad4 NFE AF: 0.0807

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0698 Hom.: 90

Bravo AF: 0.0531

Asia WGS AF: 0.0180 AC: 63 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	-0.81
Cadd	Benign	7.1
Dann	Benign	0.57
La Branchor		0.47
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: rs45572135; hg19: chr14-88400367;