rs143450927

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_014795.4(ZEB2):c.3067+6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,612,920 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 41 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 273 hom. )

Consequence

ZEB2
NM_014795.4 splice_region, intron

Scores

Splicing: ADA: 0.003162

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.18

Variant links:

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]

ZEB2 links:

ZEB2 (HGNC:):

ZEB2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 2-144396406-T-A is Benign according to our data. Variant chr2-144396406-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 95633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144396406-T-A is described in Lovd as [Benign]. Variant chr2-144396406-T-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4 linkuse as main transcript	c.3067+6A>T		splice_region_variant, intron_variant		ENST00000627532.3	NP_055610.1	O60315-1
ZEB2	NM_001171653.2 linkuse as main transcript	c.2995+6A>T		splice_region_variant, intron_variant			NP_001165124.1	O60315-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3 linkuse as main transcript	c.3067+6A>T		splice_region_variant, intron_variant		1	NM_014795.4	ENSP00000487174.1		O60315-1

Frequencies

GnomAD3 genomes

AF:

0.00715

AC:

1088

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0515

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0375

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.0173

AC:

4349

AN:

251452

Hom.:

227

AF XY:

0.0132

AC XY:

1789

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.0369

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.00422

AC:

6160

AN:

1460570

Hom.:

273

Cov.:

AF XY:

0.00364

AC XY:

2645

AN XY:

726626

show subpopulations

Gnomad4 AFR exome

AF:

0.000628

Gnomad4 AMR exome

AF:

0.0977

Gnomad4 ASJ exome

AF:

0.00122

Gnomad4 EAS exome

AF:

0.0312

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.00415

GnomAD4 genome

AF:

0.00717

AC:

1092

AN:

152350

Hom.:

Cov.:

AF XY:

0.00776

AC XY:

578

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.0518

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.0376

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.000855

Hom.:

Bravo

AF:

0.0140

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	Mar 02, 2015	This variant was interpreted as benign based on ACMG evidence categories BS1 BS2. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2024	- -

Mowat-Wilson syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 09, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0032

dbscSNV1_RF

Benign

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over