rs1555383306

Variant names:

• chr14-87982200-C-T
• rs1555383306
• NM_000153.4:c.621+5G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PP3 PP5_Moderate

The NM_000153.4(GALC):​c.621+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004241866: The variant was absent in 244428 control chromosomes. c.621+5G>A has been reported in the literature in individuals affected with Krabbe Disease (Kukita_1997). The following publication have been ascertained in the context of this evaluation (PMID:10464649). One predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant results in skipping of exon 6 (Kukita_1997).".

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALC NM_000153.4 splice_region, intron
• Scores: Splicing: ADA: 0.9940
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.25
• 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: Laboratory for Molecular Medicine, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004241866: The variant was absent in 244428 control chromosomes. c.621+5G>A has been reported in the literature in individuals affected with Krabbe Disease (Kukita_1997). The following publication have been ascertained in the context of this evaluation (PMID: 10464649). One predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant results in skipping of exon 6 (Kukita_1997).
• 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.
• PP5: Variant 14-87982200-C-T is Pathogenic according to our data. Variant chr14-87982200-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 550678.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.621+5G>A		splice_region intron	N/A	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.552+5G>A		splice_region intron	N/A	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.543+5G>A		splice_region intron	N/A	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.621+5G>A		splice_region intron	N/A	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.609+5G>A		splice_region intron	N/A	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.611+5G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1362416 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 682852

African (AFR) AF: 0.00 AC: 0 AN: 31572

American (AMR) AF: 0.00 AC: 0 AN: 43454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25344

East Asian (EAS) AF: 0.00 AC: 0 AN: 38712

South Asian (SAS) AF: 0.00 AC: 0 AN: 82850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1025046

Other (OTH) AF: 0.00 AC: 0 AN: 56890

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely 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
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		3.2
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 5

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

Other links and lift over

dbSNP: rs1555383306; hg19: chr14-88448544;