rs760471055

Positions:

• chr7-19117047-CCGCCGCCGCCGCCCG-C
• chr7-19117047-CCGCCGCCGCCGCCCG-CCGCCGCCGCCGCCCGCGCCGCCGCCGCCCG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BS1 BS2

The NM_000474.4(TWIST1):​c.260_274del​(p.Ala87_Gly91del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000108 in 1,398,748 control chromosomes in the GnomAD database, including 8 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (7 hom.)
• Consequence: TWIST1 NM_000474.4 inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.49

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a chain Twist-related protein 1 (size 201) in uniprot entity TWST1_HUMAN there are 59 pathogenic changes around while only 10 benign (86%) in NM_000474.4
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000307 (46/150060) while in subpopulation AFR AF= 0.00101 (42/41386). AF 95% confidence interval is 0.000771. There are 1 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TWIST1	NM_000474.4	c.260_274del	p.Ala87_Gly91del	inframe_deletion	1/2	ENST00000242261.6
TWIST1	NR_149001.2	n.575_589del		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TWIST1	ENST00000242261.6	c.260_274del	p.Ala87_Gly91del	inframe_deletion	1/2	1	NM_000474.4	P1
TWIST1	ENST00000354571.5	c.57_71del	p.Ala20_Gly24del	inframe_deletion, NMD_transcript_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.000307 AC: 46 AN: 149952 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000365 AC: 18 AN: 49264 Hom.: 4 AF XY: 0.000309 AC XY: 9 AN XY: 29172

Gnomad AFR exome AF: 0.00820

Gnomad AMR exome AF: 0.000882

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000419

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.000697

GnomAD4 exome AF: 0.0000841 AC: 105 AN: 1248688 Hom.: 7 AF XY: 0.0000848 AC XY: 52 AN XY: 613002

Gnomad4 AFR exome AF: 0.00225

Gnomad4 AMR exome AF: 0.000321

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000355

Gnomad4 SAS exome AF: 0.0000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000354

Gnomad4 OTH exome AF: 0.0000779

GnomAD4 genome AF: 0.000307 AC: 46 AN: 150060 Hom.: 1 Cov.: 32 AF XY: 0.000232 AC XY: 17 AN XY: 73240

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.0000662

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000204

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000297

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000332

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs760471055; hg19: chr7-19156670;