7-19117228-C-T

Position:

chr7-19117228-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BP6BS2

The NM_000474.4(TWIST1):c.94G>A(p.Gly32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,413,900 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 7 hom. )

Consequence

TWIST1
NM_000474.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 0.109

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 Likely_benign. 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

BP4

Computational evidence support a benign effect (MetaRNN=0.40579277).

BP6

Variant 7-19117228-C-T is Benign according to our data. Variant chr7-19117228-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235255.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}. Variant chr7-19117228-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWIST1	NM_000474.4 link	c.94G>A	p.Gly32Ser	missense_variant	1/2	ENST00000242261.6	NP_000465.1	Q15672
TWIST1	NR_149001.2 link	n.409G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6 link	c.94G>A	p.Gly32Ser	missense_variant	1/2	1	NM_000474.4	ENSP00000242261.5		Q15672

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

163

AN:

151162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00205

Gnomad OTH

AF:

0.000483

GnomAD3 exomes

AF:

0.00120

AC:

AN:

77226

Hom.:

AF XY:

0.00120

AC XY:

AN XY:

44284

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000395

Gnomad ASJ exome

AF:

0.000302

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000593

Gnomad FIN exome

AF:

0.000419

Gnomad NFE exome

AF:

0.00292

Gnomad OTH exome

AF:

0.000447

GnomAD4 exome

AF:

0.00249

AC:

3150

AN:

1262738

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1500

AN XY:

622590

show subpopulations

Gnomad4 AFR exome

AF:

0.000350

Gnomad4 AMR exome

AF:

0.000398

Gnomad4 ASJ exome

AF:

0.000515

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000444

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.00294

Gnomad4 OTH exome

AF:

0.00260

GnomAD4 genome

AF:

0.00108

AC:

163

AN:

151162

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

AN XY:

73786

show subpopulations

Gnomad4 AFR

AF:

0.000508

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00205

Gnomad4 OTH

AF:

0.000483

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.00117

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24127277, 26633542, 19952666, 17343269) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 09, 2023	Variant summary: TWIST1 c.94G>A (p.Gly32Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 77226 control chromosomes. This frequency does not allow conclusions about variant significance. Although c.94G>A has been reported in the literature in individuals affected with features of TWIST1-Related Disorders, it has also been reported in unaffected individuals with an author assertion as a non-pathogenic variant (example, PMID:24127277). These report(s) do not provide unequivocal conclusions about association of the variant with TWIST1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 18, 2016	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

- -

TWIST1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.27

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.69

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.37

REVEL

Uncertain

0.53

Sift

Benign

0.89

Sift4G

Benign

0.70

Polyphen

0.012

Vest4

0.69

MVP

0.99

MPC

1.4

ClinPred

0.031

GERP RS

3.7

Varity_R

0.084

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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