14-87941455-C-A

Variant names:

• chr14-87941455-C-A
• rs1360345372
• NM_000153.4:c.1774G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000153.4(GALC):​c.1774G>T​(p.Ala592Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A592T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.63
• Publications: 3 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: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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, 7 uncertain in NM_000153.4
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.1774G>T	p.Ala592Ser	missense_variant	Exon 15 of 17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.1774G>T	p.Ala592Ser	missense_variant	Exon 15 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Uncertain:1

Aug 30, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;.;.;.
Eigen	Benign	0.093
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.8	L;.;.;.
PhyloP100		2.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.23	B;B;B;.
Vest4		0.45
MutPred		0.78		Gain of catalytic residue at R590 (P = 5e-04);.;.;.;
MVP		0.93
MPC		0.23
ClinPred		0.74	D
GERP RS		4.8
Varity_R		0.092
gMVP		0.75
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1360345372; hg19: chr14-88407799;