rs1554442082

chr7-19117179-CCGCCCGCGCTG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000474.4(TWIST1):c.132_142del(p.Ser45ArgfsTer189) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TWIST1 NM_000474.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.49

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 88 pathogenic variants in the truncated region.
• PP5: Variant 7-19117179-CCGCCCGCGCTG-C is Pathogenic according to our data. Variant chr7-19117179-CCGCCCGCGCTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 543077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TWIST1	NM_000474.4	c.132_142del	p.Ser45ArgfsTer189	frameshift_variant	1/2	ENST00000242261.6
TWIST1	NR_149001.2	n.447_457del		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TWIST1	ENST00000242261.6	c.132_142del	p.Ser45ArgfsTer189	frameshift_variant	1/2	1	NM_000474.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2023

Reported in an individual with Saethre-Chotzen syndrome, described as c.128_138del11 due to alternate nomenclature (Cai et al., 2003); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 158 amino acids are lost and replaced with 188 incorrect amino acids; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24127277, 14513358, 33547006) -

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2017

For these reasons, this variant has been classified as Pathogenic. A different frameshift downstream of this variant (p.Thr137Hisfs*101) has been determined to be likely pathogenic (PMID: 24127277, Invitae). This suggests that disruptions of this region of the TWIST1 protein is causative of disease. This variant has been reported in an individual with Saethre-Chotzen syndrome-like features (PMID: 14513358). This variant is also known as 128_138del11 in the literature. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the TWIST1 gene (p.Ser45Argfs*189). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 158 amino acids of the TWIST1 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554442082; hg19: chr7-19156802;