rs1329127701
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The ENST00000373203.9(ENG):c.1134G>C(p.Ala378=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A378A) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000373203.9 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.1134G>C | p.Ala378= | splice_region_variant, synonymous_variant | 8/15 | ENST00000373203.9 | NP_001108225.1 | |
ENG | NM_000118.4 | c.1134G>C | p.Ala378= | splice_region_variant, synonymous_variant | 8/14 | NP_000109.1 | ||
ENG | NM_001278138.2 | c.588G>C | p.Ala196= | splice_region_variant, synonymous_variant | 8/15 | NP_001265067.1 | ||
ENG | NM_001406715.1 | c.1134G>C | p.Ala378= | synonymous_variant | 8/8 | NP_001393644.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.1134G>C | p.Ala378= | splice_region_variant, synonymous_variant | 8/15 | 1 | NM_001114753.3 | ENSP00000362299 | P2 | |
ENG | ENST00000344849.4 | c.1134G>C | p.Ala378= | splice_region_variant, synonymous_variant | 8/14 | 1 | ENSP00000341917 | A2 | ||
ENG | ENST00000480266.6 | c.588G>C | p.Ala196= | splice_region_variant, synonymous_variant | 8/15 | 2 | ENSP00000479015 | |||
ENG | ENST00000486329.1 | n.102G>C | splice_region_variant, non_coding_transcript_exon_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 06, 2020 | For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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: 20414677, 15517393, 21158752; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 378 of the ENG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ENG protein. This variant also falls at the last nucleotide of exon 8 of the ENG coding sequence, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.