rs118020901

Variant names:

• chr10-31521854-A-C
• rs118020901
• NM_001174096.2:c.2522A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-31521854-A-C
• chr10-31521854-A-G

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 990 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB1	NM_001174096.2	c.2522A>C	p.Gln841Pro	missense_variant	Exon 7 of 9	ENST00000424869.6	NP_001167567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB1	ENST00000424869.6	c.2522A>C	p.Gln841Pro	missense_variant	Exon 7 of 9	5	NM_001174096.2	ENSP00000415961.2

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

GnomAD2 exomes AF: 0.00744 AC: 1864 AN: 250532 AF XY: 0.00752

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 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 AC: 29 AN: 33452

Gnomad4 AMR exome AF: 0.00255 AC: 114 AN: 44702

Gnomad4 ASJ exome AF: 0.000153 AC: 4 AN: 26124

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39670

Gnomad4 SAS exome AF: 0.00391 AC: 337 AN: 86236

Gnomad4 FIN exome AF: 0.0324 AC: 1731 AN: 53408

Gnomad4 NFE exome AF: 0.00718 AC: 7986 AN: 1111876

Gnomad4 Remaining exome AF: 0.00543 AC: 328 AN: 60378

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 AC: 0.000986241 AN: 0.000986241

Gnomad4 AMR AF: 0.00294 AC: 0.00294272 AN: 0.00294272

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000386 AC: 0.000386399 AN: 0.000386399

Gnomad4 SAS AF: 0.00207 AC: 0.00207211 AN: 0.00207211

Gnomad4 FIN AF: 0.0351 AC: 0.0350745 AN: 0.0350745

Gnomad4 NFE AF: 0.00744 AC: 0.00743811 AN: 0.00743811

Gnomad4 OTH AF: 0.00521 AC: 0.00520833 AN: 0.00520833

Alfa AF: 0.00659 Hom.: 10

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

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

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. -

Jan 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Benign:2

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

not specified Benign:1

Apr 18, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.;.
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
Mutation Taster		=9/91	disease causing

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;