rs104894065

Positions:

• chr7-19117111-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000474.4(TWIST1):​c.211C>T​(p.Gln71*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TWIST1 NM_000474.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.40

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 Pathogenic. Variant got 18 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 21 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-19117111-G-A is Pathogenic according to our data. Variant chr7-19117111-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWIST1	NM_000474.4	c.211C>T	p.Gln71*	stop_gained	1/2	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2	n.526C>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6	c.211C>T	p.Gln71*	stop_gained	1/2	1	NM_000474.4	ENSP00000242261.5
TWIST1	ENST00000354571.5	n.7C>T		non_coding_transcript_exon_variant	1/3	2		ENSP00000346582.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

Alfa AF: 0.00210 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Robinow-Sorauf syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2003

- -

TWIST1-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with TWIST1-related disorder (ClinVar ID: VCV000007984 / PMID: 12791045). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TWIST1 are known to be pathogenic (PMID: 10749989). This variant has been observed in several individuals affected with Saethre-Chotzen syndrome (PMID: 12791045, 18391498, 16251895). ClinVar contains an entry for this variant (Variation ID: 7984). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Gln71*) in the TWIST1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.46	N
Vest4		0.81
GERP RS		2.8

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: rs104894065; hg19: chr7-19156734;