10-31461211-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (51 hom.)
• Consequence: ZEB1 NM_001174096.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: -0.419

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]

ACMG classification

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 [Likely_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	UniProt
ZEB1	NM_001174096.2	c.233A>C	p.Asn78Thr	missense_variant	2/9	ENST00000424869.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB1	ENST00000424869.6	c.233A>C	p.Asn78Thr	missense_variant	2/9	5	NM_001174096.2	A2

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2299 AN: 152114 Hom.: 42 Cov.: 32

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.: 21 AF XY: 0.00287 AC XY: 389 AN XY: 135406

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.: 51 Cov.: 31 AF XY: 0.00129 AC XY: 935 AN XY: 726774

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.: 43 Cov.: 32 AF XY: 0.0139 AC XY: 1035 AN XY: 74452

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.: 15

Bravo AF: 0.0173

ESP6500AA AF: 0.0495 AC: 218

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00486 AC: 590

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000297

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Corneal dystrophy, Fuchs endothelial, 6 Pathogenic:1 Benign: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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Dec 24, 2023	- -

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, criteria provided, single submitter

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

Invitae

Oct 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.52	T
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	N
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	T
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	T
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	T
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

Other links and lift over

dbSNP: rs80194531; hg19: chr10-31750140; COSMIC: COSV58055617; COSMIC: COSV58055617;