rs1009872980

Variant names:

• chr14-87992969-C-A
• rs1009872980
• NM_000153.4:c.195+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-87992969-C-A
• chr14-87992969-C-G
• chr14-87992969-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000153.4(GALC):​c.195+1G>T variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALC NM_000153.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74
• Publications: 2 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.10349854 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.195+1G>T		splice_donor_variant, intron_variant	Intron 1 of 16	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.195+1G>T		splice_donor_variant, intron_variant	Intron 1 of 16	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1367370 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 675998

African (AFR) AF: 0.00 AC: 0 AN: 27774

American (AMR) AF: 0.00 AC: 0 AN: 35848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24040

East Asian (EAS) AF: 0.00 AC: 0 AN: 32226

South Asian (SAS) AF: 0.00 AC: 0 AN: 77224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3992

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074898

Other (OTH) AF: 0.00 AC: 0 AN: 56654

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	35
DANN	Benign	0.96
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		6.7
GERP RS		1.3
PromoterAI		-0.24	Neutral
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: 16
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs1009872980; hg19: chr14-88459313;