7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCGCCCGCGCCGCC

Variant names:

Variant summary

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

The NM_000474.4(TWIST1):c.253_276dupGGCGGCGCGGGCGGCGGCGGCGGC(p.Gly92_Ser93insGlyGlyAlaGlyGlyGlyGlyGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 150,842 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TWIST1
NM_000474.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.251

Publications

3 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 40 pathogenic changes around while only 6 benign (87%) in NM_000474.4

BS2

High AC in GnomAd4 at 52 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000474.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWIST1	NM_000474.4	MANE Select	c.253_276dupGGCGGCGCGGGCGGCGGCGGCGGC	p.Gly92_Ser93insGlyGlyAlaGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 2	NP_000465.1
	TWIST1	NR_149001.2		n.568_591dupGGCGGCGCGGGCGGCGGCGGCGGC		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TWIST1	ENST00000242261.6	TSL:1 MANE Select	c.253_276dupGGCGGCGCGGGCGGCGGCGGCGGC	p.Gly92_Ser93insGlyGlyAlaGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 2	ENSP00000242261.5
TWIST1	ENST00000354571.5	TSL:2	n.49_72dupGGCGGCGCGGGCGGCGGCGGCGGC		non_coding_transcript_exon	Exon 1 of 3	ENSP00000346582.5
TWIST1	ENST00000443687.5	TSL:4	n.-147_-124dupGGCGGCGCGGGCGGCGGCGGCGGC		upstream_gene	N/A	ENSP00000416986.1

Frequencies

GnomAD3 genomes

AF:

0.000345

AC:

AN:

150740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000330

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000484

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000162

AC:

AN:

1292790

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

636940

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

25748

American (AMR)

AF:

0.00

AC:

AN:

18784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20442

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30172

South Asian (SAS)

AF:

0.00

AC:

AN:

62784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5212

European-Non Finnish (NFE)

AF:

0.00000288

AC:

AN:

1042012

Other (OTH)

AF:

0.0000748

AC:

AN:

53478

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

<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:

0.000345

AC:

AN:

150842

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

AN XY:

73642

show subpopulations

African (AFR)

AF:

0.00109

AC:

AN:

41374

American (AMR)

AF:

0.000330

AC:

AN:

15150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.000196

AC:

AN:

5098

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67454

Other (OTH)

AF:

0.000478

AC:

AN:

2090

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:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.25

Mutation Taster

=86/14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over