rs34362748

Variant names:

• chr14-87976368-C-G
• rs34362748
• NM_000153.4:c.742G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-87976368-C-G
• chr14-87976368-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000153.4(GALC):​c.742G>C​(p.Asp248His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D248N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68
• Publications: 47 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.742G>C	p.Asp248His	missense_variant	Exon 7 of 17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.742G>C	p.Asp248His	missense_variant	Exon 7 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 3713

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.96
MutPred		0.68		Gain of catalytic residue at A252 (P = 0.0032);.;.;.;
MVP		1.0
MPC		0.60
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.46
gMVP		0.96
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34362748; hg19: chr14-88442712;