NM_001174096.2:c.3G>A

Variant names:

• chr10-31319237-G-A
• rs1554797626
• NM_001174096.2:c.3G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Strong PS1_Moderate PM2 PP5_Very_Strong

The NM_001174096.2(ZEB1):​c.3G>A​(p.Met1?) variant causes a start lost 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 (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ZEB1 NM_001174096.2 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.79

Genes affected

ZEB1 (HGNC:11642): (zinc finger E-box binding homeobox 1) This gene encodes a zinc finger transcription factor. The encoded protein likely plays a role in transcriptional repression of interleukin 2. Mutations in this gene have been associated with posterior polymorphous corneal dystrophy-3 and late-onset Fuchs endothelial corneal dystrophy. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Mar 2010]

ZEB1-AS1 (HGNC:42354): (ZEB1 antisense RNA 1) This locus produces long non-coding RNA that is transcribed from a shared bi-directional promoter with zinc finger E-box binding homeobox 1 (ZEB1). This transcript binds lysine methyltransferase 2A and promotes histone modifications that are thought to promote expression of ZEB1. Expression of this gene is correlated with tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 220 codons. Genomic position: 31510846. Lost 0.195 part of the original CDS.
• PS1: Another start lost variant in NM_001174096.2 (ZEB1) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-31319237-G-A is Pathogenic according to our data. Variant chr10-31319237-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB1	NM_001174096.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 9	ENST00000424869.6	NP_001167567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB1	ENST00000424869.6	c.3G>A	p.Met1?	start_lost	Exon 1 of 9	5	NM_001174096.2	ENSP00000415961.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the ZEB1 mRNA. The next in-frame methionine is located at codon 219. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with posterior polymorphous corneal dystrophy (PMID: 17935237, 19997581, 36613650). ClinVar contains an entry for this variant (Variation ID: 488897). 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. -

Apr 20, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3 G>A pathogenic variant in the ZEB1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.3 G>A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. As this pathogenic variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. Two other variants in the Met1 position (c.1A>G and c.2T>G) have been reported in the Human Gene Mutation Database in association with posterior polymorphous corneal dystrophy (Stenson et al., 2014). We interpret c.3 G>A as a pathogenic variant. This variant has been seen apparently de novo. -

Posterior polymorphous corneal dystrophy 3;C2750448:Corneal dystrophy, Fuchs endothelial, 6 Pathogenic:1

May 23, 2023

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.;T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.92	P;.;.;.;.;.
Vest4		0.88
MutPred		0.99		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.96
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.15

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: rs1554797626; hg19: chr10-31608166;