rs2905456

Variant names:

• chr7-19064282-A-G
• rs2905456
• ENST00000443687.5:n.*90-8117T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-19064282-A-G
• chr7-19064282-A-T

Variant summary

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

The ENST00000443687.5(TWIST1):​n.*90-8117T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 152,054 control chromosomes in the GnomAD database, including 53,698 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 0.80 (53698 hom., cov: 31)
• Consequence: TWIST1 ENST00000443687.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• Publications: 0 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 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.*90-8117T>C		intron_variant	Intron 2 of 3	4		ENSP00000416986.1

Frequencies

GnomAD3 genomes AF: 0.803 AC: 122009 AN: 151936 Hom.: 53691 Cov.: 31

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.956

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.957

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.920

Gnomad FIN AF: 0.970

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.962

Gnomad OTH AF: 0.849

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

GnomAD4 genome AF: 0.803 AC: 122031 AN: 152054 Hom.: 53698 Cov.: 31 AF XY: 0.808 AC XY: 60068 AN XY: 74340

African (AFR) AF: 0.400 AC: 16562 AN: 41396

American (AMR) AF: 0.913 AC: 13925 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.957 AC: 3318 AN: 3468

East Asian (EAS) AF: 0.991 AC: 5125 AN: 5172

South Asian (SAS) AF: 0.920 AC: 4428 AN: 4814

European-Finnish (FIN) AF: 0.970 AC: 10303 AN: 10618

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.962 AC: 65448 AN: 68012

Other (OTH) AF: 0.850 AC: 1793 AN: 2110

Alfa AF: 0.875 Hom.: 17857

Bravo AF: 0.783

Asia WGS AF: 0.922 AC: 3207 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.70
PhyloP100		1.0

Splicing

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

Other links and lift over

dbSNP: rs2905456; hg19: chr7-19103905;