14-87992951-C-T
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_000153.4(GALC):c.195+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,509,366 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0032 ( 14 hom. )
Consequence
GALC
NM_000153.4 intron
NM_000153.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0400
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 14-87992951-C-T is Benign according to our data. Variant chr14-87992951-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87992951-C-T is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 14 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.195+19G>A | intron_variant | ENST00000261304.7 | NP_000144.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.195+19G>A | intron_variant | 1 | NM_000153.4 | ENSP00000261304.2 |
Frequencies
GnomAD3 genomes AF: 0.00195 AC: 297AN: 152176Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00167 AC: 190AN: 113460Hom.: 2 AF XY: 0.00165 AC XY: 105AN XY: 63670
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GnomAD4 exome AF: 0.00318 AC: 4322AN: 1357082Hom.: 14 Cov.: 33 AF XY: 0.00309 AC XY: 2068AN XY: 670198
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GnomAD4 genome AF: 0.00195 AC: 297AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111AN XY: 74460
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 18, 2020 | Variant summary: GALC c.195+19G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0017 in 113460 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in GALC causing Krabbe Disease phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.195+19G>A in individuals affected with Krabbe Disease and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Galactosylceramide beta-galactosidase deficiency Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 05, 2021 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2020 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at