10-31319235-A-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_001174096.2(ZEB1):c.1A>C(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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 29)
• Consequence: ZEB1 NM_001174096.2 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.27

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 13 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001174096.2 (ZEB1) was described as [Pathogenic] in ClinVar as 488897
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-31319235-A-C is Pathogenic according to our data. Variant chr10-31319235-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2443790.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZEB1	NM_001174096.2	c.1A>C	p.Met1?	start_lost	1/9	ENST00000424869.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB1	ENST00000424869.6	c.1A>C	p.Met1?	start_lost	1/9	5	NM_001174096.2	A2
ZEB1-AS1	ENST00000605946.1	n.177+280T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Posterior polymorphous corneal dystrophy 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T;.;.;T;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
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	0.30	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.70	P;.;.;.;.;.
Vest4		0.81
MutPred		0.99		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP		0.98
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.96
gMVP		0.10

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-31608164;