rs80194531

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001174096.2(ZEB1):c.233A>C(p.Asn78Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,224 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 43 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 51 hom. )

Consequence

ZEB1
NM_001174096.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:5

Conservation

PhyloP100: -0.419

Variant links:

Genes affected

ZEB1 (HGNC:11642): (zinc finger E-box binding homeobox 1) This gene encodes a zinc finger transcription factor. The encoded protein likely plays a role in transcriptional repression of interleukin 2. Mutations in this gene have been associated with posterior polymorphous corneal dystrophy-3 and late-onset Fuchs endothelial corneal dystrophy. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Mar 2010]

ZEB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014271468).

BP6

Variant 10-31461211-A-C is Benign according to our data. Variant chr10-31461211-A-C is described in ClinVar as [Benign]. Clinvar id is 12633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB1	NM_001174096.2 linkuse as main transcript	c.233A>C	p.Asn78Thr	missense_variant	2/9	ENST00000424869.6	NP_001167567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB1	ENST00000424869.6 linkuse as main transcript	c.233A>C	p.Asn78Thr	missense_variant	2/9	5	NM_001174096.2	ENSP00000415961	A2	P37275-2

Frequencies

GnomAD3 genomes

AF:

0.0151

AC:

2299

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0523

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0101

GnomAD3 exomes

AF:

0.00395

AC:

989

AN:

250552

Hom.:

AF XY:

0.00287

AC XY:

389

AN XY:

135406

show subpopulations

Gnomad AFR exome

AF:

0.0522

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00152

AC:

2226

AN:

1460992

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

935

AN XY:

726774

show subpopulations

Gnomad4 AFR exome

AF:

0.0525

Gnomad4 AMR exome

AF:

0.00366

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.00340

GnomAD4 genome

AF:

0.0151

AC:

2302

AN:

152232

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1035

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0522

Gnomad4 AMR

AF:

0.00621

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00995

Alfa

AF:

0.00254

Hom.:

Bravo

AF:

0.0173

ESP6500AA

AF:

0.0495

AC:

218

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00486

AC:

590

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Corneal dystrophy, Fuchs endothelial, 6

Pathogenic:1Benign:2

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	The ZEB1 gene is known as TCF8 in the published literature (PMID: 20036349). TCF8NM_030751.5:c.233A>C in the ZEB1 gene has an allele frequency of 0.052 in African subpopulation in the gnomAD database. 30 homozygous occurrences are observed in the gnomAD database. Since the Fuchs Corneal Dystrophy was reported as Late-Onset, we determined to not apply the number of homozygousity as a strong benign evidence. In addition, Riazuddin et al. reported a patient with Late-Onset Fuchs Corneal Dystrophy barboring p.N78T (PMID: 20036349). These evidence suggest the variant to be classified as benign. ACMG/AMP criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Dec 24, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

not specified

Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.083, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

ZEB1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

1.7

DANN

Benign

0.96

DEOGEN2

Benign

0.14

T;.;.;T;T;.;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.81

T;T;T;T;T;T;T

MetaRNN

Benign

0.014

T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.20

N;N;N;.;.;.;.

MutationTaster

Benign

2.9e-14

A;A;A;A;A;A;A;A;A

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.040

N;N;N;N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.050

D;D;T;T;D;T;T

Sift4G

Benign

0.17

T;T;T;T;T;T;T

Polyphen

0.013

B;.;.;.;.;.;.

Vest4

0.16

MVP

0.50

MPC

0.52

ClinPred

0.0027

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.035

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