rs749708827

Variant names:

• chr14-87939915-AACGTG-A
• rs749708827
• NM_000153.4:c.1896_1900delCACGT

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000153.4(GALC):​c.1896_1900delCACGT​(p.Thr633AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,606,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001432099: At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated almost complete loss of activity for the truncated protein (Saavedra-Matiz_2016)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L632L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GALC NM_000153.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.13
• 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001432099: At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated almost complete loss of activity for the truncated protein (Saavedra-Matiz_2016).; SCV002233062: Experimental studies have shown that this premature translational stop signal affects GALC function (PMID: 27638593).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-87939915-AACGTG-A is Pathogenic according to our data. Variant chr14-87939915-AACGTG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 555939.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.1896_1900delCACGT	p.Thr633AsnfsTer3	frameshift	Exon 16 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1827_1831delCACGT	p.Thr610AsnfsTer3	frameshift	Exon 15 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1818_1822delCACGT	p.Thr607AsnfsTer3	frameshift	Exon 16 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.1896_1900delCACGT	p.Thr633AsnfsTer3	frameshift	Exon 16 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1857_1861delCACGT	p.Thr620AsnfsTer3	frameshift	Exon 15 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1830_1834delCACGT	p.Thr611AsnfsTer3	frameshift	Exon 16 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151952 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248814 AF XY: 0.00000741

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000254 AC: 37 AN: 1455038 Hom.: 0 AF XY: 0.0000235 AC XY: 17 AN XY: 724350

⚠️ 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: 33264

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000316 AC: 35 AN: 1106332

Other (OTH) AF: 0.0000333 AC: 2 AN: 60052

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000074607), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151952 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74210

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Galactosylceramide beta-galactosidase deficiency (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs749708827; hg19: chr14-88406259;