rs1051003265

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The NM_000474.4(TWIST1):c.203G>T(p.Ser68Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000439 in 1,162,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S68N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

TWIST1
NM_000474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.41

Publications

1 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Saethre-Chotzen syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Laboratory for Molecular Medicine, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
TWIST1-related craniosynostosis
Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
isolated brachycephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated plagiocephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated scaphocephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Sweeney-Cox syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

TWIST1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a chain Twist-related protein 1 (size 201) in uniprot entity TWST1_HUMAN there are 39 pathogenic changes around while only 6 benign (87%) in NM_000474.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.057 (below the threshold of 3.09). Trascript score misZ: -0.22696 (below the threshold of 3.09). GenCC associations: The gene is linked to Saethre-Chotzen syndrome, Sweeney-Cox syndrome, isolated brachycephaly, TWIST1-related craniosynostosis, isolated plagiocephaly, isolated scaphocephaly.

BP4

Computational evidence support a benign effect (MetaRNN=0.24198636).

BS2

High AC in GnomAdExome4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST1	NM_000474.4 link	c.203G>T	p.Ser68Ile	missense_variant	Exon 1 of 2	ENST00000242261.6	NP_000465.1	Q15672
TWIST1	NR_149001.2 link	n.518G>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TWIST1	ENST00000242261.6 link	c.203G>T	p.Ser68Ile	missense_variant	Exon 1 of 2	1	NM_000474.4	ENSP00000242261.5	Q15672
TWIST1	ENST00000354571.5 link	n.-2G>T		upstream_gene_variant		2		ENSP00000346582.5	H7BY00
TWIST1	ENST00000443687.5 link	n.-197G>T		upstream_gene_variant		4		ENSP00000416986.1	H7C4D7

Frequencies

GnomAD3 genomes

AF:

0.0000204

AC:

AN:

147074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000675

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000302

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

3464

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000473

AC:

AN:

1015164

Hom.:

Cov.:

AF XY:

0.0000457

AC XY:

AN XY:

481290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20364

American (AMR)

AF:

0.00

AC:

AN:

6356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11552

East Asian (EAS)

AF:

0.00

AC:

AN:

19302

South Asian (SAS)

AF:

0.00

AC:

AN:

20134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2656

European-Non Finnish (NFE)

AF:

0.0000478

AC:

AN:

878382

Other (OTH)

AF:

0.000155

AC:

AN:

38620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000204

AC:

AN:

147074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71562

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40738

American (AMR)

AF:

0.0000675

AC:

AN:

14818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000302

AC:

AN:

66164

Other (OTH)

AF:

0.00

AC:

AN:

2036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.203G>T (p.S68I) alteration is located in exon 1 (coding exon 1) of the TWIST1 gene. This alteration results from a G to T substitution at nucleotide position 203, causing the serine (S) at amino acid position 68 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis

Uncertain:1

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TWIST1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 68 of the TWIST1 protein (p.Ser68Ile). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.34

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.3

PhyloP100

2.4

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

Sift4G

Benign

0.092

Polyphen

0.0010

Vest4

0.14

MutPred

0.19

Loss of phosphorylation at S68 (P = 0.0039);

MVP

0.95

MPC

1.6

ClinPred

0.42

GERP RS

3.1

Varity_R

0.67

gMVP

0.51

Mutation Taster

=65/35

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over