10-31319235-A-C

Variant names:

• chr10-31319235-A-C
• NM_001174096.2:c.1A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001323647.2(ZEB1):​c.-797A>C variant causes a 5 prime UTR premature start codon gain 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_001323647.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.27
• Publications: 1 publications found

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

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 10-31319235-A-C is Pathogenic according to our data. Variant chr10-31319235-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2443790.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323647.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB1	NM_001174096.2	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	NP_001167567.1	P37275-2
	ZEB1	NM_001323647.2		c.-797A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001310576.1
	ZEB1	NM_001323648.2		c.-737A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001310577.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB1	ENST00000424869.6	TSL:5 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000415961.2	P37275-2
	ZEB1	ENST00000320985.14	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000319248.9	P37275-1
	ZEB1	ENST00000558440.5	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 5	ENSP00000453970.1	H0YND9

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Posterior polymorphous corneal dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.30	D
PhyloP100		7.3
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.70	P
Vest4		0.81
MutPred		0.99		Loss of sheet (P = 0.1907)
MVP		0.98
ClinPred		0.99	D
GERP RS		4.1
PromoterAI		-0.72	Under-expression
Varity_R		0.96
gMVP		0.10
Mutation Taster		=3/197	disease causing

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

hg19: chr10-31608164;