rs1554657437
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000127.3(EXT1):c.1810G>T(p.Glu604*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
Consequence
EXT1
NM_000127.3 stop_gained
NM_000127.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 6.07
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 8-117807290-C-A is Pathogenic according to our data. Variant chr8-117807290-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 488827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117807290-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EXT1 | ENST00000378204.7 | c.1810G>T | p.Glu604* | stop_gained | 9/11 | 1 | NM_000127.3 | ENSP00000367446.3 | ||
EXT1 | ENST00000437196.1 | n.*701G>T | non_coding_transcript_exon_variant | 8/10 | 5 | ENSP00000407299.1 | ||||
EXT1 | ENST00000684189.1 | n.1277G>T | non_coding_transcript_exon_variant | 9/11 | ||||||
EXT1 | ENST00000437196.1 | n.*701G>T | 3_prime_UTR_variant | 8/10 | 5 | ENSP00000407299.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
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 | Labcorp Genetics (formerly Invitae), Labcorp | Apr 14, 2018 | This variant has been reported in an individual affected with multiple osteochondromas (PMID: 18165274). ClinVar contains an entry for this variant (Variation ID: 488827). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu604*) in the EXT1 gene. It is expected to result in an absent or disrupted protein product. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 02, 2018 | The E604X variant in the EXT1 gene has been reported previously in at least one individual with multiple exostoses (Jennes et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E604X variant is not observed in large population cohorts (Lek et al., 2016). We interpret E604X as a pathogenic variant . - |
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
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at