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7-19116906-GGCAGCGTGGGGATGATCTTCC-GGCAGCGTGGGGATGATCTTCCGCAGCGTGGGGATGATCTTCC

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM4PP3PP5_Moderate

The NM_000474.4(TWIST1):c.415_416insGGAAGATCATCCCCACGCTGC(p.Arg132_Leu138dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TWIST1
NM_000474.4 inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.83
Variant links:
Genes affected
TWIST1 (HGNC:12428): (twist family bHLH transcription factor 1) This gene encodes a basic helix-loop-helix (bHLH) transcription factor that plays an important role in embryonic development. The encoded protein forms both homodimers and heterodimers that bind to DNA E box sequences and regulate the transcription of genes involved in cranial suture closure during skull development. This protein may also regulate neural tube closure, limb development and brown fat metabolism. This gene is hypermethylated and overexpressed in multiple human cancers, and the encoded protein promotes tumor cell invasion and metastasis, as well as metastatic recurrence. Mutations in this gene cause Saethre-Chotzen syndrome in human patients, which is characterized by craniosynostosis, ptosis and hypertelorism. [provided by RefSeq, Jul 2020]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000474.4
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM4
?
    PM4 - Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
Nonframeshift variant in NON repetitive region in NM_000474.4.
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-19116906-G-GGCAGCGTGGGGATGATCTTCC is Pathogenic according to our data. Variant chr7-19116906-G-GGCAGCGTGGGGATGATCTTCC is described in ClinVar as [Pathogenic]. Clinvar id is 1457074.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TWIST1NM_000474.4 linkuse as main transcriptc.415_416insGGAAGATCATCCCCACGCTGC p.Arg132_Leu138dup inframe_insertion 1/2 ENST00000242261.6
TWIST1NR_149001.2 linkuse as main transcriptn.730_731insGGAAGATCATCCCCACGCTGC non_coding_transcript_exon_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TWIST1ENST00000242261.6 linkuse as main transcriptc.415_416insGGAAGATCATCCCCACGCTGC p.Arg132_Leu138dup inframe_insertion 1/21 NM_000474.4 P1
TWIST1ENST00000354571.5 linkuse as main transcriptc.212_213insGGAAGATCATCCCCACGCTGC p.Arg65_Leu71dup inframe_insertion, NMD_transcript_variant 1/32
TWIST1ENST00000443687.5 linkuse as main transcriptc.18_19insGGAAGATCATCCCCACGCTGC p.Leu6_Pro7insArgLysIleIleProThrLeu inframe_insertion, NMD_transcript_variant 1/44

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 30, 2020For these reasons, this variant has been classified as Pathogenic. This variant is located in a region of the TWIST1 protein where a significant number of previously reported TWIST1 in-frame insertion variants are found (PMID: 8988166, 16838304, 26114524, 31754721). These observations suggest that this may be a clinically significant region of the protein. This variant has been observed in individual(s) with TWIST1-related conditions (PMID: 21520333, Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This variant, c.395_415dup, results in the insertion of 7 amino acid(s) to the TWIST1 protein (p.Arg132_Leu138dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-19156529; API