Variant chr7-19117047-C-CCGCCGCCGCCGCCCG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP6_Very_StrongBS1BS2

The ENST00000242261.6(TWIST1):c.274_275insCGGGCGGCGGCGGCG(p.Ala87_Gly91dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 150,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TWIST1
ENST00000242261.6 inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.351

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 7-19117047-C-CCGCCGCCGCCGCCCG is Benign according to our data. Variant chr7-19117047-C-CCGCCGCCGCCGCCCG is described in ClinVar as [Likely_benign]. Clinvar id is 543080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0002 (30/150060) while in subpopulation NFE AF= 0.000267 (18/67312). AF 95% confidence interval is 0.000173. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWIST1	NM_000474.4 linkuse as main transcript	c.274_275insCGGGCGGCGGCGGCG	p.Ala87_Gly91dup	inframe_insertion	1/2	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2 linkuse as main transcript	n.589_590insCGGGCGGCGGCGGCG		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6 linkuse as main transcript	c.274_275insCGGGCGGCGGCGGCG	p.Ala87_Gly91dup	inframe_insertion	1/2	1	NM_000474.4	ENSP00000242261	P1
TWIST1	ENST00000354571.5 linkuse as main transcript	c.71_72insCGGGCGGCGGCGGCG	p.Ala20_Gly24dup	inframe_insertion, NMD_transcript_variant	1/3	2		ENSP00000346582

Frequencies

GnomAD3 genomes

AF:

0.000200

AC:

AN:

149952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000267

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000179

AC:

223

AN:

1248696

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

103

AN XY:

613016

show subpopulations

Gnomad4 AFR exome

AF:

0.000161

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000249

Gnomad4 SAS exome

AF:

0.0000179

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000204

Gnomad4 OTH exome

AF:

0.0000585

GnomAD4 genome

AF:

0.000200

AC:

AN:

150060

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73240

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000204

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000267

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Saethre-Chotzen syndrome;C1867146:Robinow-Sorauf syndrome;C4540299:Sweeney-Cox syndrome;C4551902:TWIST1-related craniosynostosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 13, 2021

- -

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over