rs2905456

Positions:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000443687.5(TWIST1):​c.*90-8117T>C variant causes a intron, NMD transcript 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, NMD_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000443687.5	c.*90-8117T>C		intron_variant, NMD_transcript_variant		4		ENSP00000416986

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

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.913

Gnomad4 ASJ AF: 0.957

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.920

Gnomad4 FIN AF: 0.970

Gnomad4 NFE AF: 0.962

Gnomad4 OTH AF: 0.850

Alfa AF: 0.871 Hom.: 7553

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2905456; hg19: chr7-19103905;