7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCCGCGCCGCC
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP6_ModerateBS1BS2
The NM_000474.4(TWIST1):c.256_276dupGGCGCGGGCGGCGGCGGCGGC(p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 150,840 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.0033 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 4 hom. )
Failed GnomAD Quality Control
Consequence
TWIST1
NM_000474.4 conservative_inframe_insertion
NM_000474.4 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.251
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 Benign. Variant got -8 ACMG points.
PM1
In a chain Twist-related protein 1 (size 201) in uniprot entity TWST1_HUMAN there are 17 pathogenic changes around while only 3 benign (85%) in NM_000474.4
BP6
Variant 7-19117045-T-TGCCGCCGCCGCCGCCCGCGCC is Benign according to our data. Variant chr7-19117045-T-TGCCGCCGCCGCCGCCCGCGCC is described in ClinVar as [Benign]. Clinvar id is 476632.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00328 (495/150840) while in subpopulation EAS AF= 0.0373 (190/5096). AF 95% confidence interval is 0.0329. There are 3 homozygotes in gnomad4. There are 265 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 495 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TWIST1 | NM_000474.4 | c.256_276dupGGCGCGGGCGGCGGCGGCGGC | p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly | conservative_inframe_insertion | 1/2 | ENST00000242261.6 | NP_000465.1 | |
TWIST1 | NR_149001.2 | n.571_591dupGGCGCGGGCGGCGGCGGCGGC | non_coding_transcript_exon_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TWIST1 | ENST00000242261.6 | c.256_276dupGGCGCGGGCGGCGGCGGCGGC | p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly | conservative_inframe_insertion | 1/2 | 1 | NM_000474.4 | ENSP00000242261.5 | ||
TWIST1 | ENST00000354571.5 | n.52_72dupGGCGCGGGCGGCGGCGGCGGC | non_coding_transcript_exon_variant | 1/3 | 2 | ENSP00000346582.5 |
Frequencies
GnomAD3 genomes AF: 0.00329 AC: 496AN: 150738Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.0000158 AC: 1AN: 63232Hom.: 0 AF XY: 0.0000269 AC XY: 1AN XY: 37154
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00126 AC: 1631AN: 1292774Hom.: 4 Cov.: 31 AF XY: 0.00114 AC XY: 723AN XY: 636930
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome AF: 0.00328 AC: 495AN: 150840Hom.: 3 Cov.: 32 AF XY: 0.00360 AC XY: 265AN XY: 73640
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ClinVar
Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at