rs1554441989
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4PP5_Very_Strong
The NM_000474.4(TWIST1):c.397_417dupAAGATCATCCCCACGCTGCCC(p.Pro139_Ser140insLysIleIleProThrLeuPro) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000474.4 conservative_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TWIST1 | NM_000474.4 | c.397_417dupAAGATCATCCCCACGCTGCCC | p.Pro139_Ser140insLysIleIleProThrLeuPro | conservative_inframe_insertion | Exon 1 of 2 | ENST00000242261.6 | NP_000465.1 | |
TWIST1 | NR_149001.2 | n.712_732dupAAGATCATCCCCACGCTGCCC | non_coding_transcript_exon_variant | Exon 1 of 3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TWIST1 | ENST00000242261.6 | c.397_417dupAAGATCATCCCCACGCTGCCC | p.Pro139_Ser140insLysIleIleProThrLeuPro | conservative_inframe_insertion | Exon 1 of 2 | 1 | NM_000474.4 | ENSP00000242261.5 | ||
TWIST1 | ENST00000354571.5 | n.193_213dupAAGATCATCCCCACGCTGCCC | non_coding_transcript_exon_variant | Exon 1 of 3 | 2 | ENSP00000346582.5 | ||||
TWIST1 | ENST00000443687.5 | n.-3_18dupAAGATCATCCCCACGCTGCCC | non_coding_transcript_exon_variant | Exon 1 of 4 | 4 | ENSP00000416986.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461836Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727230
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
TWIST1-related craniosynostosis Pathogenic:2
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This TWIST1 variant has been reported in multiple unrelated individuals with TWIST1-related disorders, including as a de novo occurrence. This variant is absent from a large population dataset but has been reported in ClinVar (Variation ID 458686). Bioinformatic analysis predicts that this in-frame duplication variant would not affect normal exon 1 splicing7, although this has not been confirmed experimentally to our knowledge. The amino acids involved in the duplication are evolutionarily conserved across most of the species assessed. We consider c.397_417dup; p.Lys133_Pro139dup in TWIST1 to be pathogenic. -
not provided Pathogenic:1
In-frame duplication of 7 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10749989, 30074960, 17621648, 11248247, 16251895, 31754721, 33937142, 16838304, 8988167) -
Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis Pathogenic:1
This variant, c.397_417dup, results in the insertion of 7 amino acid(s) of the TWIST1 protein (p.Lys133_Pro139dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of craniosynostosis (PMID: 8988167; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 458686). For these reasons, this variant has been classified as Pathogenic. -
Saethre-Chotzen syndrome Pathogenic:1
This variant, c.397_417dup, results in the insertion of 7 amino acids to the TWIST1 protein (p.Lys133_Pro139dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with craniosynostosis and was observed to arise de novo in one case (PMID: 8988167, 16838304). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This insertion is located within the conserved loop region of the basic helix-loop-helix (bHLH) domain of the TWIST1 protein. The bHLH domain is essential for protein dimerization and DNA-binding (PMID: 11992718). Four different 7 amino acid in-frame duplications in the loop region have been reported in affected individuals (PMID: 24127277, 16251895, 14513358), which suggests that insertions in this region are deleterious. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at