rs1554810510
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001114753.3(ENG):c.392del(p.Pro131ArgfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P131P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001114753.3 frameshift
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.392del | p.Pro131ArgfsTer32 | frameshift_variant | 4/15 | ENST00000373203.9 | |
ENG | NM_000118.4 | c.392del | p.Pro131ArgfsTer32 | frameshift_variant | 4/14 | ||
ENG | NM_001406715.1 | c.392del | p.Pro131ArgfsTer32 | frameshift_variant | 4/8 | ||
ENG | NM_001278138.2 | c.-155del | 5_prime_UTR_variant | 4/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.392del | p.Pro131ArgfsTer32 | frameshift_variant | 4/15 | 1 | NM_001114753.3 | P2 | |
ENG | ENST00000344849.4 | c.392del | p.Pro131ArgfsTer32 | frameshift_variant | 4/14 | 1 | A2 | ||
ENG | ENST00000480266.6 | c.-155del | 5_prime_UTR_variant | 4/15 | 2 | ||||
ENG | ENST00000462196.1 | n.292del | non_coding_transcript_exon_variant | 3/4 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461746Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727164
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Genomics And Bioinformatics Analysis Resource, Columbia University | - | - - |
Spontaneous, recurrent epistaxis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 13, 2019 | The c.392del (p.Pro131ArgfsTer32) variant identified in the ENG gene is the deletion of a single nucleotide resulting in the frameshift of the protein at amino acid 131/659 (coding exon 4/15), which is predicted to lead to the premature termination of the protein approximately 32 amino acids downstream of the variant. This variant is absent from gnomAD and ExAC, suggesting it is not a common benign variant in the populations represented in these databases. This variant is classified as Pathogenic in ClinVar (VarID:458347), and has been identified in two individuals in the literature with hereditary haemorrhagic telangiectasia [PMID: 16542389; PMID: 30251589]. This variant was identified in a proband submitted for clinical testing, and found to be inherited from an affected parent. The c.392del (p.Pro131ArgfsTer32) variant is reported here as Pathogenic. - |
Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 458347). This premature translational stop signal has been observed in individuals with epistaxis, telangiectasias and gastrointestinal bleeding (PMID: 16542389). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro131Argfs*32) 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