rs1555379155

Positions:

• chr14-87945704-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The ENST00000261304.7(GALC):​c.1519T>C​(p.Phe507Leu) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC ENST00000261304.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.08

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000261304.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4	c.1519T>C	p.Phe507Leu	missense_variant	14/17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.1519T>C	p.Phe507Leu	missense_variant	14/17	1	NM_000153.4	ENSP00000261304	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Apr 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Benign	0.38	T;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.99	D;D;D;.
Vest4		0.94
MutPred		0.71		Gain of catalytic residue at E503 (P = 0.0566);.;.;.;
MVP		0.98
MPC		0.62
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.54
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555379155; hg19: chr14-88412048;