chr7-19117045-TGCCGCCGCCGCCGCCCGC-T

Position:

• chr7-19117045-TGCCGCCGCCGCCGCCCGC-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong BS1 BS2

The ENST00000242261.6(TWIST1):​c.259_276del​(p.Ala87_Gly92del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,443,532 control chromosomes in the GnomAD database, including 126 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (123 hom.)
• Consequence: TWIST1 ENST00000242261.6 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.11

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 -14 ACMG points.

• PM1: In a chain Twist-related protein 1 (size 201) in uniprot entity TWST1_HUMAN there are 63 pathogenic changes around while only 11 benign (85%) in ENST00000242261.6
• BP6: Variant 7-19117045-TGCCGCCGCCGCCGCCCGC-T is Benign according to our data. Variant chr7-19117045-TGCCGCCGCCGCCGCCCGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 256223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00288 (435/150842) while in subpopulation EAS AF= 0.0228 (116/5098). AF 95% confidence interval is 0.0194. There are 3 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 435 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWIST1	NM_000474.4	c.259_276del	p.Ala87_Gly92del	inframe_deletion	1/2	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2	n.574_591del		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6	c.259_276del	p.Ala87_Gly92del	inframe_deletion	1/2	1	NM_000474.4	ENSP00000242261	P1
TWIST1	ENST00000354571.5	c.56_73del	p.Ala20_Gly25del	inframe_deletion, NMD_transcript_variant	1/3	2		ENSP00000346582

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 436 AN: 150740 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00165

Gnomad ASJ AF: 0.0102

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0147

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00242

GnomAD3 exomes AF: 0.00930 AC: 588 AN: 63232 Hom.: 104 AF XY: 0.00904 AC XY: 336 AN XY: 37154

Gnomad AFR exome AF: 0.00385

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.104

Gnomad SAS exome AF: 0.000928

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00219 AC: 2833 AN: 1292690 Hom.: 123 AF XY: 0.00219 AC XY: 1396 AN XY: 636884

Gnomad4 AFR exome AF: 0.000699

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0167

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.00468

GnomAD4 genome AF: 0.00288 AC: 435 AN: 150842 Hom.: 3 Cov.: 32 AF XY: 0.00333 AC XY: 245 AN XY: 73642

Gnomad4 AFR AF: 0.000532

Gnomad4 AMR AF: 0.00165

Gnomad4 ASJ AF: 0.0102

Gnomad4 EAS AF: 0.0228

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0147

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.00239

Bravo AF: 0.00216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2020

This variant is associated with the following publications: (PMID: 24166674, 15253176, 11748846, 24706433, 17343269, 16838304, 15880747) -

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

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: rs544465774; hg19: chr7-19156668;