rs118020901

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001174096.2(ZEB1):c.2522A>C(p.Gln841Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00714 in 1,613,898 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0065 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 65 hom. )

Consequence

ZEB1
NM_001174096.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:3

Conservation

PhyloP100: 7.01

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:

ZEB1 (HGNC:):

ZEB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008486122).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0065 (990/152288) while in subpopulation NFE AF= 0.00744 (506/68028). AF 95% confidence interval is 0.0069. There are 6 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 990 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB1	NM_001174096.2 linkuse as main transcript	c.2522A>C	p.Gln841Pro	missense_variant	7/9	ENST00000424869.6	NP_001167567.1	P37275-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB1	ENST00000424869.6 linkuse as main transcript	c.2522A>C	p.Gln841Pro	missense_variant	7/9	5	NM_001174096.2	ENSP00000415961.2		P37275-2F6TDF5

Frequencies

GnomAD3 genomes

AF:

0.00651

AC:

990

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0351

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00744

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00744

AC:

1864

AN:

250532

Hom.:

AF XY:

0.00752

AC XY:

1018

AN XY:

135368

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00383

Gnomad FIN exome

AF:

0.0335

Gnomad NFE exome

AF:

0.00773

Gnomad OTH exome

AF:

0.00786

GnomAD4 exome

AF:

0.00721

AC:

10531

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00713

AC XY:

5187

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.000867

Gnomad4 AMR exome

AF:

0.00255

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00391

Gnomad4 FIN exome

AF:

0.0324

Gnomad4 NFE exome

AF:

0.00718

Gnomad4 OTH exome

AF:

0.00543

GnomAD4 genome

AF:

0.00650

AC:

990

AN:

152288

Hom.:

Cov.:

AF XY:

0.00788

AC XY:

587

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0351

Gnomad4 NFE

AF:

0.00744

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00642

Hom.:

Bravo

AF:

0.00396

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00725

AC:

880

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00700

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Corneal dystrophy, Fuchs endothelial, 6

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, 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). NM_030751.5:c.2519A>C in the ZEB1 gene has an allele frequency of 0.033 in European (Finnish) subpopulation in the gnomAD database. 22 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. Gupta et al reported an individual with fuchs endothelial corneal dystrophy harboing this variant (PMID: 26622166). In addition, Riazuddin et al. reported segregation of p.Q840P mutation in a large, multigenerational FCD pedigree, and concluded this allele to be sufficient but not necessary for pathogenesis. However, the author also stated that a second, independent genetic event might account for the phenotype in the other patients having not this variant (PMID: 20036349). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	See Variant Classification Assertion Criteria. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2024

The p.Gln841Pro variant in ZEB1 is classified as likely benign because it has been identified in 3.5% (372/10606) of Finnish chromosomes, including 6 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). ACMG/AMP Criteria applied: BS1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D;D;D

MetaRNN

Benign

0.0085

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.4

N;N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.037

D;D;D;D;D

Sift4G

Benign

0.15

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.87

MVP

0.59

MPC

0.49

ClinPred

0.012

GERP RS

5.7

Varity_R

0.28

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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