rs1554810378
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate
The NM_001114753.3(ENG):c.662T>G(p.Leu221Arg) variant causes a missense 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L221P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001114753.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.662T>G | p.Leu221Arg | missense_variant | 5/15 | ENST00000373203.9 | |
ENG | NM_000118.4 | c.662T>G | p.Leu221Arg | missense_variant | 5/14 | ||
ENG | NM_001278138.2 | c.116T>G | p.Leu39Arg | missense_variant | 5/15 | ||
ENG | NM_001406715.1 | c.662T>G | p.Leu221Arg | missense_variant | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.662T>G | p.Leu221Arg | missense_variant | 5/15 | 1 | NM_001114753.3 | P2 | |
ENG | ENST00000344849.4 | c.662T>G | p.Leu221Arg | missense_variant | 5/14 | 1 | A2 | ||
ENG | ENST00000480266.6 | c.116T>G | p.Leu39Arg | missense_variant | 5/15 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu221 amino acid residue in ENG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10749981, 15880681, 16690726, 17384219, 21158752, 22991266). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ENG protein function. This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 221 of the ENG protein (p.Leu221Arg). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.