chr2-144388890-GA-G

Variant names:

• chr2-144388890-GA-G
• rs533637050
• NM_014795.4:c.*560delT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014795.4(ZEB2):​c.*560delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 297,450 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: ZEB2 NM_014795.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.34
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Mowat-Wilson syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 603 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.*560delT		3_prime_UTR_variant	Exon 10 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.*560delT		3_prime_UTR_variant	Exon 9 of 9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.*560delT		3_prime_UTR_variant	Exon 10 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes AF: 0.00510 AC: 601 AN: 117746 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.000342

Gnomad EAS AF: 0.000978

Gnomad SAS AF: 0.000761

Gnomad FIN AF: 0.00854

Gnomad MID AF: 0.00455

Gnomad NFE AF: 0.00729

Gnomad OTH AF: 0.00517

GnomAD2 exomes AF: 0.201 AC: 9968 AN: 49662 AF XY: 0.199

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.135 AC: 24322 AN: 179684 Hom.: 0 Cov.: 0 AF XY: 0.132 AC XY: 13444 AN XY: 102086

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.125 AC: 561 AN: 4494

American (AMR) AF: 0.152 AC: 2264 AN: 14884

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 916 AN: 6396

East Asian (EAS) AF: 0.132 AC: 670 AN: 5094

South Asian (SAS) AF: 0.127 AC: 4381 AN: 34432

European-Finnish (FIN) AF: 0.139 AC: 1741 AN: 12532

Middle Eastern (MID) AF: 0.0433 AC: 83 AN: 1916

European-Non Finnish (NFE) AF: 0.137 AC: 12574 AN: 91698

Other (OTH) AF: 0.137 AC: 1132 AN: 8238

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00512 AC: 603 AN: 117766 Hom.: 2 Cov.: 32 AF XY: 0.00509 AC XY: 285 AN XY: 55952

African (AFR) AF: 0.00265 AC: 85 AN: 32054

American (AMR) AF: 0.00412 AC: 46 AN: 11154

Ashkenazi Jewish (ASJ) AF: 0.000342 AC: 1 AN: 2926

East Asian (EAS) AF: 0.000982 AC: 4 AN: 4072

South Asian (SAS) AF: 0.00102 AC: 4 AN: 3926

European-Finnish (FIN) AF: 0.00854 AC: 51 AN: 5974

Middle Eastern (MID) AF: 0.00505 AC: 1 AN: 198

European-Non Finnish (NFE) AF: 0.00729 AC: 403 AN: 55244

Other (OTH) AF: 0.00513 AC: 8 AN: 1558

Alfa AF: 0.0528 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs533637050; hg19: chr2-145146457;