rs1114167349

Positions:

• chr2-144389950-T-C
• chr2-144389950-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_014795.4(ZEB2):​c.3146A>G​(p.His1049Arg) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1049P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_014795.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-144389950-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 254205.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ZEB2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant 2-144389950-T-C is Pathogenic according to our data. Variant chr2-144389950-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1026904.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.3146A>G	p.His1049Arg	missense_variant	10/10	ENST00000627532.3
ZEB2	NM_001171653.2	c.3074A>G	p.His1025Arg	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB2	ENST00000627532.3	c.3146A>G	p.His1049Arg	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 13, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of ZEB2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 1049 of the ZEB2 protein (p.His1049Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;T;T;T;.;T;D;D;T;.;D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
Polyphen		0.99	.;.;.;.;.;.;.;D;D;.;.;D;D
Vest4		0.93, 0.94, 0.94, 0.96, 0.97
MutPred		0.54		.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0206);Gain of MoRF binding (P = 0.0206);Gain of MoRF binding (P = 0.0206);.;Gain of MoRF binding (P = 0.0206);.;
MVP		0.82
MPC		2.6
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		1.0

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: rs1114167349; hg19: chr2-145147517;