7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCCGCGCCGCC

Position:

• chr7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCCGCGCCGCC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1 BP6_Moderate BS1 BS2

The NM_000474.4(TWIST1):​c.256_276dupGGCGCGGGCGGCGGCGGCGGC​(p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 150,840 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: TWIST1 NM_000474.4 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.251

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 -8 ACMG points.

• PM1: In a chain Twist-related protein 1 (size 201) in uniprot entity TWST1_HUMAN there are 17 pathogenic changes around while only 3 benign (85%) in NM_000474.4
• BP6: Variant 7-19117045-T-TGCCGCCGCCGCCGCCCGCGCC is Benign according to our data. Variant chr7-19117045-T-TGCCGCCGCCGCCGCCCGCGCC is described in ClinVar as [Benign]. Clinvar id is 476632.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00328 (495/150840) while in subpopulation EAS AF= 0.0373 (190/5096). AF 95% confidence interval is 0.0329. There are 3 homozygotes in gnomad4. There are 265 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 495 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWIST1	NM_000474.4	c.256_276dupGGCGCGGGCGGCGGCGGCGGC	p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly	conservative_inframe_insertion	1/2	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2	n.571_591dupGGCGCGGGCGGCGGCGGCGGC		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6	c.256_276dupGGCGCGGGCGGCGGCGGCGGC	p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly	conservative_inframe_insertion	1/2	1	NM_000474.4	ENSP00000242261.5
TWIST1	ENST00000354571.5	n.52_72dupGGCGCGGGCGGCGGCGGCGGC		non_coding_transcript_exon_variant	1/3	2		ENSP00000346582.5

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 496 AN: 150738 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.00793

Gnomad ASJ AF: 0.000871

Gnomad EAS AF: 0.0373

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000979

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.0000158 AC: 1 AN: 63232 Hom.: 0 AF XY: 0.0000269 AC XY: 1 AN XY: 37154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00126 AC: 1631 AN: 1292774 Hom.: 4 Cov.: 31 AF XY: 0.00114 AC XY: 723 AN XY: 636930

Gnomad4 AFR exome AF: 0.000699

Gnomad4 AMR exome AF: 0.000266

Gnomad4 ASJ exome AF: 0.000294

Gnomad4 EAS exome AF: 0.00371

Gnomad4 SAS exome AF: 0.000207

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00131

Gnomad4 OTH exome AF: 0.00198

GnomAD4 genome AF: 0.00328 AC: 495 AN: 150840 Hom.: 3 Cov.: 32 AF XY: 0.00360 AC XY: 265 AN XY: 73640

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00785

Gnomad4 ASJ AF: 0.000871

Gnomad4 EAS AF: 0.0373

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0000979

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00144

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2025

- -

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;