rs760471055

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BS2

The NM_000474.4(TWIST1):c.260_274delCGGGCGGCGGCGGCG(p.Ala87_Gly91del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000108 in 1,398,748 control chromosomes in the GnomAD database, including 8 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 7 hom. )

Consequence

TWIST1
NM_000474.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.49

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: Likely_benign. The variant received -2 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

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST1	NM_000474.4 link	c.260_274delCGGGCGGCGGCGGCG	p.Ala87_Gly91del	disruptive_inframe_deletion	Exon 1 of 2	ENST00000242261.6	NP_000465.1	Q15672
TWIST1	NR_149001.2 link	n.575_589delCGGGCGGCGGCGGCG		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_274delCGGGCGGCGGCGGCG	p.Ala87_Gly91del	disruptive_inframe_deletion	Exon 1 of 2	1	NM_000474.4	ENSP00000242261.5	Q15672
TWIST1	ENST00000354571.5 link	n.56_70delCGGGCGGCGGCGGCG		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000346582.5	H7BY00
TWIST1	ENST00000443687.5 link	n.-140_-126delCGGGCGGCGGCGGCG		upstream_gene_variant		4		ENSP00000416986.1	H7C4D7

Frequencies

GnomAD3 genomes

AF:

0.000307

AC:

AN:

149952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

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:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000365

AC:

AN:

49264

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.00820

Gnomad AMR exome

AF:

0.000882

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000419

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000129

Gnomad OTH exome

AF:

0.000697

GnomAD4 exome

AF:

0.0000841

AC:

105

AN:

1248688

Hom.:

AF XY:

0.0000848

AC XY:

AN XY:

613002

show subpopulations

African (AFR)

AF:

0.00225

AC:

AN:

24878

American (AMR)

AF:

0.000321

AC:

AN:

15596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18702

East Asian (EAS)

AF:

0.0000355

AC:

AN:

28164

South Asian (SAS)

AF:

0.0000359

AC:

AN:

55772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31140

Middle Eastern (MID)

AF:

0.000200

AC:

AN:

4998

European-Non Finnish (NFE)

AF:

0.0000354

AC:

AN:

1018118

Other (OTH)

AF:

0.0000779

AC:

AN:

51320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.551

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000307

AC:

AN:

150060

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

AN XY:

73240

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41386

American (AMR)

AF:

0.0000662

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:

0.0000297

AC:

AN:

67312

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000332

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.5

Mutation Taster

=174/26

disease causing (fs/PTC)

(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

Computational scores

Splicing

Publications

Other links and lift over