rs2717329

Variant names:

• chr7-19023152-G-A
• rs2717329
• ENST00000443687.5:n.*205-2051C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000443687.5(TWIST1):​n.*205-2051C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 152,142 control chromosomes in the GnomAD database, including 20,467 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (20467 hom., cov: 32)
• Consequence: TWIST1 ENST00000443687.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.567
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000443687.5	n.*205-2051C>T		intron_variant	Intron 3 of 3	4		ENSP00000416986.1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69337 AN: 152024 Hom.: 20413 Cov.: 32

Gnomad AFR AF: 0.853

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.411

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.456 AC: 69442 AN: 152142 Hom.: 20467 Cov.: 32 AF XY: 0.454 AC XY: 33769 AN XY: 74372

African (AFR) AF: 0.853 AC: 35420 AN: 41504

American (AMR) AF: 0.353 AC: 5385 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1208 AN: 3472

East Asian (EAS) AF: 0.256 AC: 1322 AN: 5172

South Asian (SAS) AF: 0.349 AC: 1684 AN: 4826

European-Finnish (FIN) AF: 0.311 AC: 3297 AN: 10590

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 19997 AN: 67986

Other (OTH) AF: 0.406 AC: 858 AN: 2112

Alfa AF: 0.331 Hom.: 5634

Bravo AF: 0.473

Asia WGS AF: 0.294 AC: 1024 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.73
DANN	Benign	0.24
PhyloP100		-0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2717329; hg19: chr7-19062775;