7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP6BS2

The NM_000474.4(TWIST1):c.256_276delGGCGCGGGCGGCGGCGGCGGC(p.Gly86_Gly92del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,443,484 control chromosomes in the GnomAD database, including 2 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

TWIST1
NM_000474.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.11

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 -3 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

BP6

Variant 7-19117045-TGCCGCCGCCGCCGCCCGCGCC-T is Benign according to our data. Variant chr7-19117045-TGCCGCCGCCGCCGCCCGCGCC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 931278.

BS2

High AC in GnomAd4 at 6 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.256_276delGGCGCGGGCGGCGGCGGCGGC	p.Gly86_Gly92del	conservative_inframe_deletion	Exon 1 of 2	NP_000465.1
	TWIST1	NR_149001.2		n.571_591delGGCGCGGGCGGCGGCGGCGGC		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.256_276delGGCGCGGGCGGCGGCGGCGGC	p.Gly86_Gly92del	conservative_inframe_deletion	Exon 1 of 2	ENSP00000242261.5
TWIST1	ENST00000354571.5	TSL:2	n.52_72delGGCGCGGGCGGCGGCGGCGGC		non_coding_transcript_exon	Exon 1 of 3	ENSP00000346582.5
TWIST1	ENST00000443687.5	TSL:4	n.-144_-124delGGCGCGGGCGGCGGCGGCGGC		upstream_gene	N/A	ENSP00000416986.1

Frequencies

GnomAD3 genomes

AF:

0.0000398

AC:

AN:

150738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000889

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000949

AC:

AN:

63232

AF XY:

0.0000807

show subpopulations

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:

0.000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

143

AN:

1292746

Hom.:

AF XY:

0.000121

AC XY:

AN XY:

636908

show subpopulations

African (AFR)

AF:

0.000117

AC:

AN:

25748

American (AMR)

AF:

0.0000532

AC:

AN:

18780

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20434

East Asian (EAS)

AF:

0.00

AC:

AN:

30168

South Asian (SAS)

AF:

0.00

AC:

AN:

62774

European-Finnish (FIN)

AF:

0.0000293

AC:

AN:

34156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5212

European-Non Finnish (NFE)

AF:

0.000131

AC:

137

AN:

1041996

Other (OTH)

AF:

0.0000187

AC:

AN:

53478

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.0000398

AC:

AN:

150738

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

73528

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41260

American (AMR)

AF:

0.00

AC:

AN:

15130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000889

AC:

AN:

67462

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Sweeney-Cox syndrome (1)

TWIST1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Mutation Taster

=175/25

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over