rs886042057

Variant names:

• chr14-87992970-C-G
• rs886042057
• NM_000153.4:c.195G>C
• GALC p.Gly65Gly

Your query was ambiguous. Multiple possible variants found:

• chr14-87992970-C-G
• chr14-87992970-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PP3_Strong PP5_Very_Strong

The NM_000153.4(GALC):​c.195G>C​(p.Gly65Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,520,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000964060: Studies have shown that this variant results in abnormal splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID:8940268)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G65G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: GALC NM_000153.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.10
• Publications: 4 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: Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Myriad Women's Health

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000964060: Studies have shown that this variant results in abnormal splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 8940268).; SCV001443768: Functional studies support a damaging effect of this variant on splicing (PMID: 8940268).; SCV002819635: The variant was absent in 125252 control chromosomes. c.195G>C has been reported in the literature in individuals affected with slowly progressive/late onset Krabbe Disease (example, De Gasperi_1996, Bernardini_1997, Debs_2013). These data indicate that the variant is likely to be associated with disease. Internal structural analysis indicates that this variant affects mRNA splicing resulting in first 126 bases of intron 1 inserted in-frame between nucleotides 195 and 196 (legacy nucleotides 147 and 148) (exactly at the junction of exons 1 and 2), because of the activation of a cryptic splice site (De Gasperi_1996).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 14-87992970-C-G is Pathogenic according to our data. Variant chr14-87992970-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.195G>C	p.Gly65Gly	splice_region synonymous	Exon 1 of 17	NP_000144.2	P54803-1
	GALC	NM_001424072.1		c.-76G>C		splice_region	Exon 1 of 18	NP_001411001.1
	GALC	NM_001424075.1		c.-242G>C		splice_region	Exon 1 of 18	NP_001411004.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.195G>C	p.Gly65Gly	splice_region synonymous	Exon 1 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.183G>C	p.Gly61Gly	splice_region synonymous	Exon 1 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.185G>C		splice_region non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1367970 Hom.: 0 Cov.: 33 AF XY: 0.00000444 AC XY: 3 AN XY: 676338

African (AFR) AF: 0.000216 AC: 6 AN: 27802

American (AMR) AF: 0.00 AC: 0 AN: 35918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24042

East Asian (EAS) AF: 0.00 AC: 0 AN: 32274

South Asian (SAS) AF: 0.00 AC: 0 AN: 77270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34792

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075202

Other (OTH) AF: 0.00 AC: 0 AN: 56678

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74462

African (AFR) AF: 0.000361 AC: 15 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000117

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Galactosylceramide beta-galactosidase deficiency (4)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.90
PhyloP100		3.1
PromoterAI		-0.17	Neutral
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: 0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886042057;

hg19: chr14-88459314;