7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCCGCGCCGCC

Variant names:

• chr7-19117045-T-TGCCGCCGCCGCCGCCCGCGCC
• rs544465774
• NM_000474.4:c.256_276dupGGCGCGGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.251
• Publications: 3 publications found

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]

TWIST1 Gene-Disease associations (from GenCC):

• Saethre-Chotzen syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Laboratory for Molecular Medicine, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• TWIST1-related craniosynostosis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• isolated brachycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated plagiocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated scaphocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sweeney-Cox syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM1: In a chain Twist-related protein 1 (size 201) in uniprot entity TWST1_HUMAN there are 40 pathogenic changes around while only 6 benign (87%) 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/Likely_benign. ClinVar VariationId is 476632.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 = 0.00328 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 495 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000474.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWIST1	NM_000474.4	MANE Select	c.256_276dupGGCGCGGGCGGCGGCGGCGGC	p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 2	NP_000465.1
	TWIST1	NR_149001.2		n.571_591dupGGCGCGGGCGGCGGCGGCGGC		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWIST1	ENST00000242261.6	TSL:1 MANE Select	c.256_276dupGGCGCGGGCGGCGGCGGCGGC	p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 2	ENSP00000242261.5
	TWIST1	ENST00000354571.5	TSL:2	n.52_72dupGGCGCGGGCGGCGGCGGCGGC		non_coding_transcript_exon	Exon 1 of 3	ENSP00000346582.5
	TWIST1	ENST00000443687.5	TSL:4	n.-144_-124dupGGCGCGGGCGGCGGCGGCGGC		upstream_gene	N/A	ENSP00000416986.1

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

GnomAD2 exomes AF: 0.0000158 AC: 1 AN: 63232 AF XY: 0.0000269

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 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

African (AFR) AF: 0.000699 AC: 18 AN: 25748

American (AMR) AF: 0.000266 AC: 5 AN: 18784

Ashkenazi Jewish (ASJ) AF: 0.000294 AC: 6 AN: 20442

East Asian (EAS) AF: 0.00371 AC: 112 AN: 30168

South Asian (SAS) AF: 0.000207 AC: 13 AN: 62784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34158

Middle Eastern (MID) AF: 0.000192 AC: 1 AN: 5212

European-Non Finnish (NFE) AF: 0.00131 AC: 1370 AN: 1042000

Other (OTH) AF: 0.00198 AC: 106 AN: 53478

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

African (AFR) AF: 0.00118 AC: 49 AN: 41374

American (AMR) AF: 0.00785 AC: 119 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.000871 AC: 3 AN: 3446

East Asian (EAS) AF: 0.0373 AC: 190 AN: 5096

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4816

European-Finnish (FIN) AF: 0.0000979 AC: 1 AN: 10212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00147 AC: 99 AN: 67454

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.000651 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25
Mutation Taster		=86/14	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs544465774; hg19: chr7-19156668;