chr9-127826659-A-G
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM5BP4BS2
The NM_001114753.3(ENG):c.374T>C(p.Val125Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V125D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001114753.3 missense
Scores
Clinical Significance
Conservation
Publications
- telangiectasia, hereditary hemorrhagic, type 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
- hereditary hemorrhagic telangiectasiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- juvenile polyposis syndromeInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.374T>C | p.Val125Ala | missense_variant | Exon 4 of 15 | ENST00000373203.9 | NP_001108225.1 | |
ENG | NM_000118.4 | c.374T>C | p.Val125Ala | missense_variant | Exon 4 of 14 | NP_000109.1 | ||
ENG | NM_001406715.1 | c.374T>C | p.Val125Ala | missense_variant | Exon 4 of 8 | NP_001393644.1 | ||
ENG | NM_001278138.2 | c.-173T>C | 5_prime_UTR_variant | Exon 4 of 15 | NP_001265067.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 151984Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000199 AC: 5AN: 250866 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461542Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727044 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000263 AC: 4AN: 151984Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74226 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband; ExAC: 1/66342 European -
Telangiectasia, hereditary hemorrhagic, type 1 Uncertain:1
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not provided Uncertain:1
Reported in a proband with epistaxis and pulmonary AVM in the published literature; however, this proband also harbors an additional ENG variant (PMID: 21158752); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27146957, 21158752) -
Hereditary hemorrhagic telangiectasia Uncertain:1
This missense change has been observed in individual(s) with epistaxis, pulmonary arteriovenous malformation, or polyps (PMID: 21158752, 27146957). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt ENG protein function. ClinVar contains an entry for this variant (Variation ID: 402828). This variant is present in population databases (rs750115837, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 125 of the ENG protein (p.Val125Ala). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at