2-144388890-GAAAA-GAAAAAAA

Variant names:

• chr2-144388890-G-GAAA
• rs533637050
• NM_014795.4:c.*558_*560dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014795.4(ZEB2):​c.*558_*560dupTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 215,030 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ZEB2 NM_014795.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.*558_*560dupTTT		3_prime_UTR_variant	Exon 10 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.*558_*560dupTTT		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.*558_*560dupTTT		3_prime_UTR_variant	Exon 10 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000262 AC: 13 AN: 49662 AF XY: 0.000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000510

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000302

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000349

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 30 AN: 215030 Hom.: 0 Cov.: 0 AF XY: 0.000105 AC XY: 13 AN XY: 124330

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

African (AFR) AF: 0.000201 AC: 1 AN: 4972

American (AMR) AF: 0.000181 AC: 3 AN: 16600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7746

East Asian (EAS) AF: 0.000506 AC: 3 AN: 5926

South Asian (SAS) AF: 0.000145 AC: 6 AN: 41258

European-Finnish (FIN) AF: 0.0000696 AC: 1 AN: 14378

Middle Eastern (MID) AF: 0.000480 AC: 1 AN: 2084

European-Non Finnish (NFE) AF: 0.000134 AC: 15 AN: 112326

Other (OTH) AF: 0.00 AC: 0 AN: 9740

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs533637050; hg19: chr2-145146457;