NM_000153.4:c.349A>T

Variant names:

• chr14-87986582-T-A
• rs145580093
• NM_000153.4:c.349A>T

Variant summary

Our verdict is Pathogenic. The variant received 29 ACMG points: 29P and 0B. PS1_Very_Strong PS3 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000153.4(GALC):​c.349A>T​(p.Met117Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002246036: Studies have shown that this missense change alters GALC gene expression (PMID:8940268)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M117V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.99
• 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 29 ACMG points.

• PS1: Transcript NM_000153.4 (GALC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002246036: Studies have shown that this missense change alters GALC gene expression (PMID: 8940268).; SCV003934324: The most pronounced variant effect results in 20% of normal galactocerebrosidase activity in-vitro (De Gaspieri_1996) and a 94% reduction in GALC activity in the brain homogenate of the individual reported above (Iacono_2022 citing De Gaspieri_1996). PMID: 8940268, 21876145, 36113749
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000153.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-87986582-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92504.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant 14-87986582-T-A is Pathogenic according to our data. Variant chr14-87986582-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1458657.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.349A>T	p.Met117Leu	missense	Exon 4 of 17	NP_000144.2	P54803-1
	GALC	NM_001424076.1		c.-319A>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 18	NP_001411005.1
	GALC	NM_001424077.1		c.-319A>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 18	NP_001411006.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.349A>T	p.Met117Leu	missense	Exon 4 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.337A>T	p.Met113Leu	missense	Exon 4 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.339A>T		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Galactosylceramide beta-galactosidase deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		8.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.76		Gain of catalytic residue at E113 (P = 0.002)
MVP		0.88
MPC		0.57
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.88
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs145580093; hg19: chr14-88452926;