7-19117045-TGCCGCCGCCGCCGCCCGCGCCGCC-TGCCGCCGCCGCCGCCCGCGCCGCCGCCGCCGCCGCCCGCGCCGCC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP6_ModerateBS1BS2

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

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.251
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
TWIST1NM_000474.4 linkc.256_276dupGGCGCGGGCGGCGGCGGCGGC p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly conservative_inframe_insertion 1/2 ENST00000242261.6 NP_000465.1 Q15672
TWIST1NR_149001.2 linkn.571_591dupGGCGCGGGCGGCGGCGGCGGC non_coding_transcript_exon_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TWIST1ENST00000242261.6 linkc.256_276dupGGCGCGGGCGGCGGCGGCGGC p.Gly92_Ser93insGlyAlaGlyGlyGlyGlyGly conservative_inframe_insertion 1/21 NM_000474.4 ENSP00000242261.5 Q15672
TWIST1ENST00000354571.5 linkn.52_72dupGGCGCGGGCGGCGGCGGCGGC non_coding_transcript_exon_variant 1/32 ENSP00000346582.5 H7BY00

Frequencies

GnomAD3 genomes
AF:
0.00329
AC:
496
AN:
150738
Hom.:
3
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024- -

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.

Other links and lift over

dbSNP: rs544465774; hg19: chr7-19156668; API