12-63780075-TCCCCGCGGGGCCTCAGGAAGGGGGCGGC-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014254.3(RXYLT1):c.123_150delGGGCCTCAGGAAGGGGGCGGCCCCCGCG(p.Leu43fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,597,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
RXYLT1
NM_014254.3 frameshift
NM_014254.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.22
Genes affected
RXYLT1 (HGNC:13530): (ribitol xylosyltransferase 1) This gene encodes a type II transmembrane protein that is thought to have glycosyltransferase function. Mutations in this gene result in cobblestone lissencephaly. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]
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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 12-63780075-TCCCCGCGGGGCCTCAGGAAGGGGGCGGC-T is Pathogenic according to our data. Variant chr12-63780075-TCCCCGCGGGGCCTCAGGAAGGGGGCGGC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 452154.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 |
---|---|---|---|---|---|---|---|---|
RXYLT1 | NM_014254.3 | c.123_150delGGGCCTCAGGAAGGGGGCGGCCCCCGCG | p.Leu43fs | frameshift_variant | 1/6 | ENST00000261234.11 | NP_055069.1 | |
RXYLT1 | XM_047428079.1 | c.123_150delGGGCCTCAGGAAGGGGGCGGCCCCCGCG | p.Leu43fs | frameshift_variant | 1/5 | XP_047284035.1 | ||
RXYLT1 | NM_001278237.2 | c.-991_-964delGGGCCTCAGGAAGGGGGCGGCCCCCGCG | 5_prime_UTR_variant | 1/6 | NP_001265166.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151688Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000159 AC: 23AN: 1446120Hom.: 0 AF XY: 0.0000167 AC XY: 12AN XY: 719404
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151688Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74068
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Leu43Argfs*37) in the RXYLT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RXYLT1 are known to be pathogenic (PMID: 23217329, 23519211, 31742715). This variant is present in population databases (rs748590408, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with RXYLT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452154). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2023 | Frameshift 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 significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at