rs121909187
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000474.4(TWIST1):c.368C>A(p.Ser123Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,410 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S123S) has been classified as Likely benign.
Frequency
Consequence
NM_000474.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TWIST1 | NM_000474.4 | c.368C>A | p.Ser123Ter | stop_gained | 1/2 | ENST00000242261.6 | |
TWIST1 | NR_149001.2 | n.683C>A | non_coding_transcript_exon_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TWIST1 | ENST00000242261.6 | c.368C>A | p.Ser123Ter | stop_gained | 1/2 | 1 | NM_000474.4 | P1 | |
TWIST1 | ENST00000354571.5 | c.167C>A | p.Ser56Ter | stop_gained, NMD_transcript_variant | 1/3 | 2 | |||
TWIST1 | ENST00000443687.5 | upstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461410Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727042
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 29, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Saethre-Chotzen syndrome (PMID: 8988167). The variant is also known as p.S127Ter. ClinVar contains an entry for this variant (Variation ID: 7976). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser123*) in the TWIST1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TWIST1 are known to be pathogenic (PMID: 10749989). - |
Saethre-Chotzen syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 26, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at