rs387906954

Variant names:

• chr14-87965585-G-A
• rs387906954
• NM_000153.4:c.953C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-87965585-G-A
• chr14-87965585-G-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000153.4(GALC):​c.953C>T​(p.Pro318Leu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P318A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.96
• Publications: 10 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

LOC124903355 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 5 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 chr14-87965586-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 370631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.914
• PP5: Variant 14-87965585-G-A is Pathogenic according to our data. Variant chr14-87965585-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2579652.Status of the report is criteria_provided_single_submitter, 1 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.953C>T	p.Pro318Leu	missense	Exon 9 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.884C>T	p.Pro295Leu	missense	Exon 8 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.875C>T	p.Pro292Leu	missense	Exon 9 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.953C>T	p.Pro318Leu	missense	Exon 9 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.941C>T	p.Pro314Leu	missense	Exon 9 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.943C>T		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Galactosylceramide beta-galactosidase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		10
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.80
Sift	Benign	0.067	T
Sift4G	Uncertain	0.056	T
Polyphen		0.96	D
Vest4		0.83
MutPred		0.70		Gain of catalytic residue at Q316 (P = 0)
MVP		0.99
MPC		0.58
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.84
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs387906954; hg19: chr14-88431929;