7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCCGCGCCGCC

Position:

• chr7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCCGCGCCGCC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000474.4(TWIST1):​c.276_277insGGCGCGGGCGGCGGCGGCGGCGGCGCGGGCGGCGGCGGCGGC​(p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGlyGlyAlaGlyGlyGlyGlyGly) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000663 in 150,740 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TWIST1 NM_000474.4 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 4 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
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWIST1	NM_000474.4	c.276_277insGGCGCGGGCGGCGGCGGCGGCGGCGCGGGCGGCGGCGGCGGC	p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGlyGlyAlaGlyGlyGlyGlyGly	inframe_insertion	1/2	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2	n.591_592insGGCGCGGGCGGCGGCGGCGGCGGCGCGGGCGGCGGCGGCGGC		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6	c.276_277insGGCGCGGGCGGCGGCGGCGGCGGCGCGGGCGGCGGCGGCGGC	p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGlyGlyAlaGlyGlyGlyGlyGly	inframe_insertion	1/2	1	NM_000474.4	ENSP00000242261	P1
TWIST1	ENST00000354571.5	c.73_74insGGCGCGGGCGGCGGCGGCGGCGGCGCGGGCGGCGGCGGCGGC	p.Gly25_Ser26insGlyAlaGlyGlyGlyGlyGlyGlyAlaGlyGlyGlyGlyGly	inframe_insertion, NMD_transcript_variant	1/3	2		ENSP00000346582

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150740 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150740 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73528

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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: rs544465774; hg19: chr7-19156668;