Genetic Variant ZEB1:p.Gln841Arg (chr10-31521854-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001174096.2(ZEB1):c.2522A>G(p.Gln841Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q841P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ZEB1
NM_001174096.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.01

Publications

29 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

posterior polymorphous corneal dystrophy 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Fuchs' endothelial dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
posterior polymorphous corneal dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
corneal dystrophy, Fuchs endothelial, 6
Inheritance: AD Classification: LIMITED Submitted by: G2P

ZEB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3998798).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174096.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZEB1	NM_001174096.2	MANE Select	c.2522A>G	p.Gln841Arg	missense	Exon 7 of 9	NP_001167567.1
ZEB1	NM_030751.6		c.2519A>G	p.Gln840Arg	missense	Exon 7 of 9	NP_110378.3
ZEB1	NM_001323676.2		c.2480A>G	p.Gln827Arg	missense	Exon 7 of 9	NP_001310605.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZEB1	ENST00000424869.6	TSL:5 MANE Select	c.2522A>G	p.Gln841Arg	missense	Exon 7 of 9	ENSP00000415961.2
ZEB1	ENST00000320985.14	TSL:1	c.2519A>G	p.Gln840Arg	missense	Exon 7 of 9	ENSP00000319248.9
ZEB1	ENST00000437844.6	TSL:1	n.*2659A>G		non_coding_transcript_exon	Exon 9 of 11	ENSP00000405958.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250532

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

M_CAP

Benign

0.012

MetaRNN

Benign

0.40

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

7.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.33

Sift

Benign

0.041

Sift4G

Uncertain

0.060

Polyphen

0.99

Vest4

0.37

MutPred

0.52

Gain of solvent accessibility (P = 0.0128)

MVP

0.65

MPC

0.13

ClinPred

0.43

GERP RS

5.7

Varity_R

0.17

gMVP

0.52

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over