rs1555383517

Variant names:

• chr14-87984454-AT-A
• rs1555383517
• NM_000153.4:c.521delA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000153.4(GALC):​c.521delA​(p.Tyr174LeufsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y174Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC NM_000153.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.99
• Publications: 1 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: Laboratory for Molecular Medicine, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-87984454-AT-A is Pathogenic according to our data. Variant chr14-87984454-AT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 552100.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000153.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.521delA	p.Tyr174LeufsTer3	frameshift	Exon 5 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.452delA	p.Tyr151LeufsTer3	frameshift	Exon 4 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.443delA	p.Tyr148LeufsTer3	frameshift	Exon 5 of 17	NP_001188331.1	P54803-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.521delA	p.Tyr174LeufsTer3	frameshift	Exon 5 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.509delA	p.Tyr170fs	frameshift	Exon 5 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.511delA		non_coding_transcript_exon	Exon 5 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Galactosylceramide beta-galactosidase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555383517; hg19: chr14-88450798;