rs1363815113
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000127.3(EXT1):c.2101C>T(p.Arg701Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,870 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
EXT1
NM_000127.3 stop_gained
NM_000127.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.64
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 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-117799852-G-A is Pathogenic according to our data. Variant chr8-117799852-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117799852-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXT1 | NM_000127.3 | c.2101C>T | p.Arg701Ter | stop_gained | 11/11 | ENST00000378204.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXT1 | ENST00000378204.7 | c.2101C>T | p.Arg701Ter | stop_gained | 11/11 | 1 | NM_000127.3 | P1 | |
EXT1 | ENST00000684189.1 | n.1568C>T | non_coding_transcript_exon_variant | 11/11 | |||||
EXT1 | ENST00000684443.1 | n.2227C>T | non_coding_transcript_exon_variant | 2/2 | |||||
EXT1 | ENST00000437196.1 | c.*992C>T | 3_prime_UTR_variant, NMD_transcript_variant | 10/10 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250454Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135394
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727238
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | EXT1: PM2, PVS1:Moderate, PS2:Supporting, PS4:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 21, 2020 | Nonsense 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: 11170095, 18976157, 26690531, 12032595) - |
Multiple congenital exostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2023 | This sequence change creates a premature translational stop signal (p.Arg701*) in the EXT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the EXT1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary multiple osteochondromas (PMID: 11170095, 26690531). ClinVar contains an entry for this variant (Variation ID: 488691). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Exostoses, multiple, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Jul 21, 2023 | The EXT1 c.2101C>T (p.Arg701*) variant has been reported in at least three individuals affected with multiple exostoses (Kojima H et al., PMID: 18976157; Seki H et al., PMID: 11170095; Tanteles GA et al., PMID: 26690531). This variant has been reported in the ClinVar database as a germline pathogenic variant by 3 submitters. This variant is only observed on 1/250,454 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant introduces a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay but is expected to remove ~6% of the protein including the glycosyl transferase domain. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 45
Find out detailed SpliceAI scores and Pangolin per-transcript scores at