7-19117228-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS2

The NM_000474.4(TWIST1):c.94G>A(p.Gly32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,413,900 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G32R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 7 hom. )

Consequence

TWIST1
NM_000474.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 0.109

Publications

2 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=0.40579277).

BP6

Variant 7-19117228-C-T is Benign according to our data. Variant chr7-19117228-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235255.

BS2

High AC in GnomAd4 at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST1	NM_000474.4 link	c.94G>A	p.Gly32Ser	missense_variant	Exon 1 of 2	ENST00000242261.6	NP_000465.1	Q15672
TWIST1	NR_149001.2 link	n.409G>A		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 link	c.94G>A	p.Gly32Ser	missense_variant	Exon 1 of 2	1	NM_000474.4	ENSP00000242261.5		Q15672
TWIST1	ENST00000354571.5 link	n.-111G>A		upstream_gene_variant		2		ENSP00000346582.5		H7BY00

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

163

AN:

151162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

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:

0.00205

Gnomad OTH

AF:

0.000483

GnomAD2 exomes

AF:

0.00120

AC:

AN:

77226

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000395

Gnomad ASJ exome

AF:

0.000302

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000419

Gnomad NFE exome

AF:

0.00292

Gnomad OTH exome

AF:

0.000447

GnomAD4 exome

AF:

0.00249

AC:

3150

AN:

1262738

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1500

AN XY:

622590

show subpopulations

African (AFR)

AF:

0.000350

AC:

AN:

25716

American (AMR)

AF:

0.000398

AC:

AN:

25156

Ashkenazi Jewish (ASJ)

AF:

0.000515

AC:

AN:

21362

East Asian (EAS)

AF:

0.00

AC:

AN:

25986

South Asian (SAS)

AF:

0.0000444

AC:

AN:

67572

European-Finnish (FIN)

AF:

0.000337

AC:

AN:

29668

Middle Eastern (MID)

AF:

0.000554

AC:

AN:

3610

European-Non Finnish (NFE)

AF:

0.00294

AC:

2973

AN:

1012896

Other (OTH)

AF:

0.00260

AC:

132

AN:

50772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

165

330

496

661

826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<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:

0.00108

AC:

163

AN:

151162

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

AN XY:

73786

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

41348

American (AMR)

AF:

0.000132

AC:

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00205

AC:

139

AN:

67720

Other (OTH)

AF:

0.000483

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000139

Hom.:

Bravo

AF:

0.00117

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 07, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24127277, 26633542, 19952666, 17343269) -

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TWIST1: PP2, PP3, BS1 -

not specified

Uncertain:1Benign:1

Mar 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TWIST1 c.94G>A (p.Gly32Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 77226 control chromosomes. This frequency does not allow conclusions about variant significance. Although c.94G>A has been reported in the literature in individuals affected with features of TWIST1-Related Disorders, it has also been reported in unaffected individuals with an author assertion as a non-pathogenic variant (example, PMID:24127277). These report(s) do not provide unequivocal conclusions about association of the variant with TWIST1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

May 18, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Saethre-Chotzen syndrome;C1867146:Robinow-Sorauf syndrome;C4540299:Sweeney-Cox syndrome;C4551902:TWIST1-related craniosynostosis

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis

Benign:1

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TWIST1-related disorder

Benign:1

Mar 01, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.27

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.69

PhyloP100

0.11

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.37

REVEL

Uncertain

0.53

Sift

Benign

0.89

Sift4G

Benign

0.70

Polyphen

0.012

Vest4

0.69

MVP

0.99

MPC

1.4

ClinPred

0.031

GERP RS

3.7

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.084

gMVP

0.25

Mutation Taster

=74/26

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

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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