chr14-87986552-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000153.4(GALC):​c.379C>T​(p.Arg127Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000434 in 1,613,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

GALC
NM_000153.4 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.31
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-87986552-G-A is Pathogenic according to our data. Variant chr14-87986552-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 429982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GALCNM_000153.4 linkuse as main transcriptc.379C>T p.Arg127Ter stop_gained 4/17 ENST00000261304.7 NP_000144.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GALCENST00000261304.7 linkuse as main transcriptc.379C>T p.Arg127Ter stop_gained 4/171 NM_000153.4 ENSP00000261304 P1P54803-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152010
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
249360
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135276
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000530
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000452
AC:
66
AN:
1461590
Hom.:
0
Cov.:
30
AF XY:
0.0000426
AC XY:
31
AN XY:
727114
show subpopulations
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:
0.0000576
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152010
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74240
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000164
Hom.:
0
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000241
AC:
2
ExAC
AF:
0.0000331
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 18, 2018This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with Krabbe disease [PMID 20886637] -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterApr 27, 2023PVS1, PS3, PM2 -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Feb 20, 2021- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2024This sequence change creates a premature translational stop signal (p.Arg127*) in the GALC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs200532368, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with autosomal recessive Krabbe disease (PMID: 20886637, 21824559, 27638593). This variant is also known as p.R111X. ClinVar contains an entry for this variant (Variation ID: 429982). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 28, 2016Variant summary: The c.379C>T (p.Arg127*) variant in GALC gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant has been reported in several affected individuals presented with infantile form of Krabbe via published reports. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0032% exclusively in individuals of European descent (0.06%). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in GALC gene (0.22%). Taken together, the variant was classified as Pathogenic. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 08, 2019Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 20886637, 23319190, 26795590, 27638593) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityApr 03, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.62
CADD
Pathogenic
48
DANN
Uncertain
1.0
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.92
D
MutationTaster
Benign
1.0
A;A;A;A
Vest4
0.83
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200532368; hg19: chr14-88452896; COSMIC: COSV54326049; COSMIC: COSV54326049; API