rs1554441993

Positions:

• chr7-19116913-T-TG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000474.4(TWIST1):​c.408dupC​(p.Thr137fs) variant causes a frameshift 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: Genomes: not found (cov: 32)
• Consequence: TWIST1 NM_000474.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.87

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]

TWIST1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-19116913-T-TG is Pathogenic according to our data. Variant chr7-19116913-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 543076.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWIST1	NM_000474.4	c.408dupC	p.Thr137fs	frameshift_variant	1/2	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2	n.723dupC		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6	c.408dupC	p.Thr137fs	frameshift_variant	1/2	1	NM_000474.4	ENSP00000242261.5
TWIST1	ENST00000354571.5	n.204dupC		non_coding_transcript_exon_variant	1/3	2		ENSP00000346582.5
TWIST1	ENST00000443687.5	n.9dupC		non_coding_transcript_exon_variant	1/4	4		ENSP00000416986.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2019

This variant results in an extension of the TWIST1 protein. Other variant(s) that result in a similarly extended protein product (p.Gln147Serfs*91) have been determined to be pathogenic (PMID: 24127277). This suggests that these extensions are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individuals affected with Saethre-Chotzen syndrome (PMID: 24127277). This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the TWIST1 gene (p.Thr137Hisfs*101). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acids of the TWIST1 protein and extend the protein by an additional 35 amino acids. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554441993; hg19: chr7-19156536;