7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCCGCC

Variant names:

• chr7-19117045-TGCCGCCGCCGCCGCCCGC-T
• rs544465774
• NM_000474.4:c.259_276delGCGGGCGGCGGCGGCGGC

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.259_276delGCGGGCGGCGGCGGCGGC​(p.Ala87_Gly92del) variant causes a conservative 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (123 hom.)
• Consequence: TWIST1 NM_000474.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.11
• 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-TGCCGCCGCCGCCGCCCGC-T is Benign according to our data. Variant chr7-19117045-TGCCGCCGCCGCCGCCCGC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 435 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.259_276delGCGGGCGGCGGCGGCGGC	p.Ala87_Gly92del	conservative_inframe_deletion	Exon 1 of 2	NP_000465.1
	TWIST1	NR_149001.2		n.574_591delGCGGGCGGCGGCGGCGGC		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.259_276delGCGGGCGGCGGCGGCGGC	p.Ala87_Gly92del	conservative_inframe_deletion	Exon 1 of 2	ENSP00000242261.5
	TWIST1	ENST00000354571.5	TSL:2	n.55_72delGCGGGCGGCGGCGGCGGC		non_coding_transcript_exon	Exon 1 of 3	ENSP00000346582.5
	TWIST1	ENST00000443687.5	TSL:4	n.-141_-124delGCGGGCGGCGGCGGCGGC		upstream_gene	N/A	ENSP00000416986.1

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

GnomAD2 exomes AF: 0.00930 AC: 588 AN: 63232 AF XY: 0.00904

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 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

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

American (AMR) AF: 0.00304 AC: 57 AN: 18780

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 229 AN: 20436

East Asian (EAS) AF: 0.0167 AC: 504 AN: 30170

South Asian (SAS) AF: 0.00116 AC: 73 AN: 62762

European-Finnish (FIN) AF: 0.0111 AC: 379 AN: 34156

Middle Eastern (MID) AF: 0.00192 AC: 10 AN: 5212

European-Non Finnish (NFE) AF: 0.00126 AC: 1313 AN: 1041954

Other (OTH) AF: 0.00468 AC: 250 AN: 53472

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

African (AFR) AF: 0.000532 AC: 22 AN: 41374

American (AMR) AF: 0.00165 AC: 25 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 35 AN: 3446

East Asian (EAS) AF: 0.0228 AC: 116 AN: 5098

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.0147 AC: 150 AN: 10212

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00119 AC: 80 AN: 67454

Other (OTH) AF: 0.00239 AC: 5 AN: 2090

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.00216

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	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		3.1
Mutation Taster		=185/15	polymorphism (auto)

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; COSMIC: COSV54250335; COSMIC: COSV54250335;