14-87993044-C-A

Position:

• chr14-87993044-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000153.4(GALC):​c.121G>T​(p.Gly41Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. G41S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73

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 7 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, 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 chr14-87993044-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30621.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.121G>T	p.Gly41Cys	missense_variant	1/17	ENST00000261304.7
GALC	NM_001201401.2	c.121G>T	p.Gly41Cys	missense_variant	1/16
GALC	NM_001201402.2	c.117+339G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.121G>T	p.Gly41Cys	missense_variant	1/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1404310 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 694604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.
Eigen	Benign	-0.010
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.81	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.035	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		1.0	D;.
Vest4		0.58
MutPred		0.68		Gain of catalytic residue at G41 (P = 0.0123);Gain of catalytic residue at G41 (P = 0.0123);
MVP		0.96
MPC		0.51
ClinPred		0.91	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.15
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906955; hg19: chr14-88459388;