rs1554441991

chr7-19116905-G-GGGCAGCGTGGGGATGATCTTC

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000474.4(TWIST1):c.416_417insGAAGATCATCCCCACGCTGCC(p.Lys133_Pro139dup) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.83

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 15 ACMG points.

• PM1: 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: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000474.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-19116905-G-GGGCAGCGTGGGGATGATCTTC is Pathogenic according to our data. Variant chr7-19116905-G-GGGCAGCGTGGGGATGATCTTC is described in ClinVar as [Pathogenic]. Clinvar id is 543075.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.416_417insGAAGATCATCCCCACGCTGCC	p.Lys133_Pro139dup	inframe_insertion	1/2	ENST00000242261.6
TWIST1	NR_149001.2	n.731_732insGAAGATCATCCCCACGCTGCC		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TWIST1	ENST00000242261.6	c.416_417insGAAGATCATCCCCACGCTGCC	p.Lys133_Pro139dup	inframe_insertion	1/2	1	NM_000474.4	P1
TWIST1	ENST00000354571.5	c.213_214insGAAGATCATCCCCACGCTGCC	p.Lys66_Pro72dup	inframe_insertion, NMD_transcript_variant	1/3	2
TWIST1	ENST00000443687.5	c.19_20insGAAGATCATCCCCACGCTGCC	p.Pro7_Ser8insLysIleIleProThrLeuPro	inframe_insertion, NMD_transcript_variant	1/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2019

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 27, 2022

For these reasons, this variant has been classified as Pathogenic. 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). Two different 7 amino acid in-frame duplications in the loop region have been reported in individuals affected with Saethre-Chotzen syndrome (PMID: 16251895, 14513358) and a different variant (c.397_417dup21) giving rise to the same protein effect observed here (p.Lys133_Pro139dup) has also been reported in an individual affected with Saethre-Chotzen syndrome (PMID: 8988167, 16251895), which suggests that insertions in this region are deleterious. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 543075). This variant is also known as "type 1 duplication", "416ins21" and "416_417dup21" (PMID: 8988167, 8988166, 14513358). This variant has been observed in individual(s) with Saethre-Chotzen syndrome (PMID: 8988166, 8988167, 11992718, 14513358, 16251895, 19755431, 20643727). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.396_416dup, 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. -

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: rs1554441991; hg19: chr7-19156528;