rs1060501419
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001114753.3(ENG):c.904G>T(p.Glu302Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E302E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001114753.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.904G>T | p.Glu302Ter | stop_gained | 7/15 | ENST00000373203.9 | |
ENG | NM_000118.4 | c.904G>T | p.Glu302Ter | stop_gained | 7/14 | ||
ENG | NM_001278138.2 | c.358G>T | p.Glu120Ter | stop_gained | 7/15 | ||
ENG | NM_001406715.1 | c.904G>T | p.Glu302Ter | stop_gained | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.904G>T | p.Glu302Ter | stop_gained | 7/15 | 1 | NM_001114753.3 | P2 | |
ENG | ENST00000344849.4 | c.904G>T | p.Glu302Ter | stop_gained | 7/14 | 1 | A2 | ||
ENG | ENST00000480266.6 | c.358G>T | p.Glu120Ter | stop_gained | 7/15 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 28
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 28
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 10, 2017 | The ENG c.904G>T; p.Glu302Ter variant (rs1060501419) has been described in an individual with symptoms of HHT (McDonald 2011), is reported as pathogenic in ClinVar (Variation ID: 407132), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA that is subject to nonsense mediated decay. Taken together, this variant is considered pathogenic. REFERENCES McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. - |
Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2020 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 21158752, Invitae). ClinVar contains an entry for this variant (Variation ID: 407132). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu302*) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at