chr8-117819743-AG-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000127.3(EXT1):c.1468del(p.Leu490TrpfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
EXT1
NM_000127.3 frameshift
NM_000127.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.06
Genes affected
EXT1 (HGNC:3512): (exostosin glycosyltransferase 1) This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of multiple exostoses. [provided by RefSeq, Jul 2008]
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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 8-117819743-AG-A is Pathogenic according to our data. Variant chr8-117819743-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 265130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117819743-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr8-117819743-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr8-117819743-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXT1 | NM_000127.3 | c.1468del | p.Leu490TrpfsTer9 | frameshift_variant | 6/11 | ENST00000378204.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXT1 | ENST00000378204.7 | c.1468del | p.Leu490TrpfsTer9 | frameshift_variant | 6/11 | 1 | NM_000127.3 | P1 | |
EXT1 | ENST00000684189.1 | n.935del | non_coding_transcript_exon_variant | 6/11 | |||||
EXT1 | ENST00000437196.1 | c.*359del | 3_prime_UTR_variant, NMD_transcript_variant | 5/10 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461120Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726864
GnomAD4 exome
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1461120
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31
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1
AN XY:
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple congenital exostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265130). This premature translational stop signal has been observed in individuals with multiple exostoses (PMID: 10713884, 17301954). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu490Trpfs*9) in the EXT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2015 | The c.1468delC pathogenic variant in the EXT1 gene has been reported previously in association with hereditary multiple exostoses (Dobson-Stone et al., 2000; Signori et al., 2007; Sarrión et al., 2013). The deletion causes a frameshift starting with codon Leucine 490, changes this amino acid to a Tryptophan residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Leu490TrpfsX9. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1468delC variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at