rs137852981

chr2-144399104-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014795.4(ZEB2):c.2083C>T(p.Arg695Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R695R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 2.56

Genes affected

ZEB2 (HGNC:14881): (zinc finger E-box binding homeobox 2) The protein encoded by this gene is a member of the Zfh1 family of 2-handed zinc finger/homeodomain proteins. It is located in the nucleus and functions as a DNA-binding transcriptional repressor that interacts with activated SMADs. Mutations in this gene are associated with Hirschsprung disease/Mowat-Wilson syndrome. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-144399104-G-A is Pathogenic according to our data. Variant chr2-144399104-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144399104-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZEB2	NM_014795.4	c.2083C>T	p.Arg695Ter	stop_gained	8/10	ENST00000627532.3
ZEB2	NM_001171653.2	c.2011C>T	p.Arg671Ter	stop_gained	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB2	ENST00000627532.3	c.2083C>T	p.Arg695Ter	stop_gained	8/10	1	NM_014795.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004755 / PMID: 11592033). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 27, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant was previously reported as pathogenic and was found once in our laboratory in a 17-year-old male with intellectual disability, absent speech, epilepsy, self-injury, aortic stenosis, hypospadias, Hirschsprung disease, quadriplegic cerebral palsy. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2001	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The p.Arg695Ter variant in ZEB2 was identified by our study in one individual with global developmental delay and agenesis of the corpus callosum. Trio exome analysis showed this variant to be de novo. The p.Arg695Ter variant in ZEB2 has been previously reported in 16 unrelated individuals with Mowat Wilson syndrome (PMID: 33510600, PMID: 32196960, PMID: 27831545, PMID: 15908750, PMID: 11592033, PMID: 31285160, PMID: 26809768, PMID: 11279515, PMID: 17932455, PMID: 24401652). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 7 individuals with confirmed paternity and maternity (PMID: 33510600, PMID: 15908750, PMID: 11592033, PMID: 11279515, PMID: 24401652). This variant has also been reported in ClinVar (Variation ID: 4755) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 695, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the ZEB2 gene is an established disease mechanism in autosomal dominant Mowat Wilson syndrome. In summary, this variant meets criteria to be classified as pathogenic for Mowat Wilson syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS4, PM2_Supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2020	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ZEB2 are known to be pathogenic (PMID: 16053902). This variant has been observed in several individuals affected with Mowat-Wilson syndrome (PMID: 27831545, 17932455, 26809768, 19842203, 17958891) including many de novo observations (PMID: 11592033, 15908750, 24401652, 26993267). This variant is also known as c.2083C>T (p.R925X), and this gene is also known as the SIP1 and ZFHX1B in the literature. ClinVar contains an entry for this variant (Variation ID: 4755). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg695*) in the ZEB2 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia	Oct 20, 2023	Heterozygous variant associated with Mowat-Wilson syndrome in various individuals (de novo / germline mosaicism). ACMG/AMP criteria PVS1, PS2, PM2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	Mar 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24401652, 17932455, 11279515, 26809768, 23891399, 31285160, 25525159, 11592033, 15908750, 27831545, 32196960, 33510600) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	38
Dann	Uncertain	0.99
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.94, 0.94, 0.93, 0.94, 0.94
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs137852981; hg19: chr2-145156671; COSMIC: COSV57956692; COSMIC: COSV57956692;