rs118020901

chr10-31521854-A-Cchr10-31521854-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:3
• Conservation: PhyloP100: 7.01

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 -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. This position pass quality control queck.
• BS2: High AC in GnomAd at 990 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZEB1	NM_001174096.2	c.2522A>C	p.Gln841Pro	missense_variant	7/9	ENST00000424869.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB1	ENST00000424869.6	c.2522A>C	p.Gln841Pro	missense_variant	7/9	5	NM_001174096.2	A2

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 990 AN: 152170 Hom.: 6 Cov.: 32

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.: 17 AF XY: 0.00752 AC XY: 1018 AN XY: 135368

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.: 65 Cov.: 31 AF XY: 0.00713 AC XY: 5187 AN XY: 727098

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.: 6 Cov.: 32 AF XY: 0.00788 AC XY: 587 AN XY: 74458

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.: 5

Bravo AF: 0.00396

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00725 AC: 880

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00700

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Corneal dystrophy, Fuchs endothelial, 6 Pathogenic:1 Uncertain: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	Invitae	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	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
MetaRNN	Benign	0.0085	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.63	T
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	T
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

Other links and lift over

dbSNP: rs118020901; hg19: chr10-31810782; COSMIC: COSV100313557; COSMIC: COSV100313557;