dbSNP rs565371578: TWIST1:p.Val60Val (chr7-19117142-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000474.4(TWIST1):c.180C>T(p.Val60Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,095,286 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 3 hom. )

Consequence

TWIST1
NM_000474.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.713

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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Laboratory for Molecular Medicine
TWIST1-related craniosynostosis
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 7-19117142-G-A is Benign according to our data. Variant chr7-19117142-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 476630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.713 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00602 (886/147198) while in subpopulation AFR AF = 0.0203 (831/40926). AF 95% confidence interval is 0.0192. There are 7 homozygotes in GnomAd4. There are 424 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 886 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.180C>T	p.Val60Val	synonymous	Exon 1 of 2	NP_000465.1	Q15672
	TWIST1	NR_149001.2		n.495C>T		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TWIST1	ENST00000242261.6	TSL:1 MANE Select	c.180C>T	p.Val60Val	synonymous	Exon 1 of 2	ENSP00000242261.5	Q15672
TWIST1	ENST00000354571.5	TSL:2	n.-25C>T		upstream_gene	N/A	ENSP00000346582.5	H7BY00
TWIST1	ENST00000443687.5	TSL:4	n.-220C>T		upstream_gene	N/A	ENSP00000416986.1	H7C4D7

Frequencies

GnomAD3 genomes

AF:

0.00599

AC:

881

AN:

147098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00277

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:

0.0000907

Gnomad OTH

AF:

0.00394

GnomAD2 exomes

AF:

0.00

AC:

AN:

370

AF XY:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000744

AC:

705

AN:

948088

Hom.:

Cov.:

AF XY:

0.000733

AC XY:

328

AN XY:

447314

show subpopulations

African (AFR)

AF:

0.0244

AC:

455

AN:

18644

American (AMR)

AF:

0.00176

AC:

AN:

4542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9010

East Asian (EAS)

AF:

0.00

AC:

AN:

12618

South Asian (SAS)

AF:

0.0000546

AC:

AN:

18304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12450

Middle Eastern (MID)

AF:

0.00309

AC:

AN:

2262

European-Non Finnish (NFE)

AF:

0.000197

AC:

165

AN:

835712

Other (OTH)

AF:

0.00200

AC:

AN:

34546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00602

AC:

886

AN:

147198

Hom.:

Cov.:

AF XY:

0.00591

AC XY:

424

AN XY:

71696

show subpopulations

African (AFR)

AF:

0.0203

AC:

831

AN:

40926

American (AMR)

AF:

0.00277

AC:

AN:

14826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3382

East Asian (EAS)

AF:

0.00

AC:

AN:

5062

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000907

AC:

AN:

66134

Other (OTH)

AF:

0.00390

AC:

AN:

2052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

138

184

230

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:

0.000349

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.9

(source)

DANN

Benign

0.95

PhyloP100

0.71

PromoterAI

0.038

Neutral

(source)

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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