7-19116972-T-C

Variant names:

• chr7-19116972-T-C
• rs1554442016
• NM_000474.4:c.350A>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000474.4(TWIST1):​c.350A>G​(p.Glu117Gly) variant causes a missense change. 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 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.03

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 10 ACMG points.

• PM1: In a domain bHLH (size 51) in uniprot entity TWST1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000474.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 7-19116972-T-C is Pathogenic according to our data. Variant chr7-19116972-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 444876.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST1	NM_000474.4	c.350A>G	p.Glu117Gly	missense_variant	Exon 1 of 2	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2	n.665A>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6	c.350A>G	p.Glu117Gly	missense_variant	Exon 1 of 2	1	NM_000474.4	ENSP00000242261.5
TWIST1	ENST00000354571.5	n.146A>G		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000346582.5
TWIST1	ENST00000443687.5	n.-50A>G		upstream_gene_variant		4		ENSP00000416986.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Sep 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 117 of the TWIST1 protein (p.Glu117Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TWIST1-related conditions (PMID: 28369379). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 444876). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TWIST1 function (PMID: 28369379). This variant disrupts the p.Glu117 amino acid residue in TWIST1. Other variant(s) that disrupt this residue have been observed in individuals with TWIST1-related conditions (PMID: 27884935, 28369379, 30450715), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Sweeney-Cox syndrome Pathogenic:1

Oct 26, 2017

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.91		Gain of MoRF binding (P = 0.0678);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		2.1
Varity_R		0.91
gMVP		1.0

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: rs1554442016; hg19: chr7-19156595;