14-87986580-CAT-GAG

Variant names:

• chr14-87986580-CAT-GAG
• NM_000153.4:c.349_351delATGinsCTC
• GALC p.Met117Leu

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PS1_Moderate

The NM_001424074.1(GALC):​c.1_3delATGinsCTC​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC NM_001424074.1 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29
• 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: Genomics England PanelApp, G2P, ClinGen, Myriad Women's Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 14 pathogenic variants. Next in-frame start position is after 18 codons. Genomic position: 87986531. Lost 0.030 part of the original CDS.
• PS1: Another start lost variant in NM_001424074.1 (GALC) was described as [Likely_pathogenic] in ClinVar

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424074.1. 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.349_351delATGinsCTC	p.Met117Leu	missense	N/A	NP_000144.2	P54803-1
	GALC	NM_001424074.1		c.1_3delATGinsCTC	p.Met1?	start_lost	N/A	NP_001411003.1
	GALC	NM_001424075.1		c.1_3delATGinsCTC	p.Met1?	start_lost	N/A	NP_001411004.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.349_351delATGinsCTC	p.Met117Leu	missense	N/A	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.337_339delATGinsCTC	p.Met113Leu	missense	N/A	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.339_341delATGinsCTC		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

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

hg19: chr14-88452924;