7-19117047-CCGCCGCCGCCGCCCG-CCGCCGCCGCCGCCCGCGCCGCCGCCGCCCG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1BP6_Very_StrongBS2

The NM_000474.4(TWIST1):c.260_274dupCGGGCGGCGGCGGCG(p.Ala87_Gly91dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 150,060 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TWIST1
NM_000474.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.351

Publications

0 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: Benign. The variant received -10 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

BP6

Variant 7-19117047-C-CCGCCGCCGCCGCCCG is Benign according to our data. Variant chr7-19117047-C-CCGCCGCCGCCGCCCG is described in ClinVar as [Likely_benign]. Clinvar id is 543080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST1	NM_000474.4 link	c.260_274dupCGGGCGGCGGCGGCG	p.Ala87_Gly91dup	conservative_inframe_insertion	Exon 1 of 2	ENST00000242261.6	NP_000465.1	Q15672
TWIST1	NR_149001.2 link	n.575_589dupCGGGCGGCGGCGGCG		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.260_274dupCGGGCGGCGGCGGCG	p.Ala87_Gly91dup	conservative_inframe_insertion	Exon 1 of 2	1	NM_000474.4	ENSP00000242261.5	Q15672
TWIST1	ENST00000354571.5 link	n.56_70dupCGGGCGGCGGCGGCG		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000346582.5	H7BY00
TWIST1	ENST00000443687.5 link	n.-140_-126dupCGGGCGGCGGCGGCG		upstream_gene_variant		4		ENSP00000416986.1	H7C4D7

Frequencies

GnomAD3 genomes

AF:

0.000200

AC:

AN:

149952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000267

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000179

AC:

223

AN:

1248696

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

103

AN XY:

613016

show subpopulations

African (AFR)

AF:

0.000161

AC:

AN:

24880

American (AMR)

AF:

0.00

AC:

AN:

15596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18702

East Asian (EAS)

AF:

0.000249

AC:

AN:

28164

South Asian (SAS)

AF:

0.0000179

AC:

AN:

55782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4998

European-Non Finnish (NFE)

AF:

0.000204

AC:

208

AN:

1018114

Other (OTH)

AF:

0.0000585

AC:

AN:

51318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000200

AC:

AN:

150060

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73240

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41386

American (AMR)

AF:

0.000132

AC:

AN:

15112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3382

East Asian (EAS)

AF:

0.000204

AC:

AN:

4904

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000267

AC:

AN:

67312

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

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

Benign:1

Jul 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis

Benign:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.35

Mutation Taster

=81/19

polymorphism

(source)

Splicing

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