rs397515448

chr2-144389885-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_014795.4(ZEB2):c.3211T>C(p.Ser1071Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a zinc_finger_region C2H2-type 8; atypical (size 21) in uniprot entity ZEB2_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_014795.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ZEB2
• PP5: Variant 2-144389885-A-G is Pathogenic according to our data. Variant chr2-144389885-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56826.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZEB2	NM_014795.4	c.3211T>C	p.Ser1071Pro	missense_variant	10/10	ENST00000627532.3
ZEB2	NM_001171653.2	c.3139T>C	p.Ser1047Pro	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB2	ENST00000627532.3	c.3211T>C	p.Ser1071Pro	missense_variant	10/10	1	NM_014795.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2021

The c.3211T>C (p.S1071P) alteration is located in exon 10 (coding exon 9) of the ZEB2 gene. This alteration results from a T to C substitution at nucleotide position 3211, causing the serine (S) at amino acid position 1071 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD), the ZEB2 c.3211T>C alteration was not observed, with coverage at this position. This alteration has been reported in a patient with moderate intellectual disability and the facial gestalt suggestive of Mowat Wilson syndrome. The patient was reported to have seizures, onset at 2 years 9 months, but no other congenital anomalies and had a normal brain MRI (Ghoumid, 2013). Another patient with this alteration was reported to have mild intellectual disability, epilepsy, language delay, a happy demeanor, constipation and mild dysmorphic features (Wenger, 2014). This amino acid position is highly conserved in available vertebrate species. The p.S1071P amino acid is located within the highly conserved C-zinc-finger (C-ZF) domain of ZEB2 (Ghoumid, 2013). The ZF domains function to bind target-promoter DNA needed for transactivation of the protein. In vitro functional analysis on the E-cadherin promoter showed that the integrity of ZEB2 C-ZF is necessary for proper DNA-binding and transactivation activities of the protein (Ghoumid, 2013). The zebrafish in vivo model was used to show that human ZEB2 mRNAs carrying the p.S1071P alteration could variably rescue sip1b morphant embryos and suggested that ZEB2 function was not restricted to repression of the E-cadherin (Ghoumid, 2013). The in silico prediction for the p.S1071P alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Mowat-Wilson syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;T;T;.;T;D;D;T;.;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
Polyphen		0.99	.;.;.;.;.;.;.;D;D;.;.;D;D
Vest4		0.77, 0.79, 0.86, 0.92, 0.87
MutPred		0.16		.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0673);Loss of MoRF binding (P = 0.0673);Loss of MoRF binding (P = 0.0673);.;Loss of MoRF binding (P = 0.0673);.;
MVP		0.63
MPC		2.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.99

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: rs397515448; hg19: chr2-145147452;