14-87982205-C-T

Variant names:

• chr14-87982205-C-T
• rs1428763453
• NM_000153.4:c.621G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000153.4(GALC):​c.621G>A​(p.Lys207Lys) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GALC NM_000153.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6
• Conservation: PhyloP100: 7.28
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Krabbe disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.621G>A	p.Lys207Lys	splice_region_variant, synonymous_variant	Exon 6 of 17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.621G>A	p.Lys207Lys	splice_region_variant, synonymous_variant	Exon 6 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246890 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1392774 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 696814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32188

American (AMR) AF: 0.00 AC: 0 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25600

East Asian (EAS) AF: 0.00 AC: 0 AN: 39060

South Asian (SAS) AF: 0.00 AC: 0 AN: 84442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050408

Other (OTH) AF: 0.0000172 AC: 1 AN: 58012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:1 Uncertain:4

Jun 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with clinical features of Krabbe disease (PMID: 10833326, 26795590). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 550179). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects codon 207 of the GALC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GALC protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. -

Dec 23, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Enzyme deficiency -

Aug 26, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 07, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GALC c.621G>A (p.Lys207Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 243894 control chromosomes (gnomAD). c.621G>A has been reported in the literature in a homozygous individual affected with Krabbe Disease (Wenger_2000), and in a newborn screening sample indicative of low GALC enzyme activity, where the a second mutation was not provided (Orsini_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GALC: PM2, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.92
PhyloP100		7.3
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1428763453; hg19: chr14-88448549;