dbSNP rs118020901: ZEB1:p.Gln841Pro (chr10-31521854-A-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001174096.2(ZEB1):c.2522A>C(p.Gln841Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00714 in 1,613,898 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0065 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 65 hom. )

Consequence

ZEB1
NM_001174096.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:4

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: Labcorp Genetics (formerly Invitae), G2P
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008486122).

BP6

Variant 10-31521854-A-C is Benign according to our data. Variant chr10-31521854-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12634.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0065 (990/152288) while in subpopulation NFE AF = 0.00744 (506/68028). AF 95% confidence interval is 0.0069. There are 6 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 990 AD gene.

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	UniProt
ZEB1	NM_001174096.2	MANE Select	c.2522A>C	p.Gln841Pro	missense	Exon 7 of 9	NP_001167567.1	P37275-2
ZEB1	NM_030751.6		c.2519A>C	p.Gln840Pro	missense	Exon 7 of 9	NP_110378.3
ZEB1	NM_001323676.2		c.2480A>C	p.Gln827Pro	missense	Exon 7 of 9	NP_001310605.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZEB1	ENST00000424869.6	TSL:5 MANE Select	c.2522A>C	p.Gln841Pro	missense	Exon 7 of 9	ENSP00000415961.2	P37275-2
ZEB1	ENST00000320985.14	TSL:1	c.2519A>C	p.Gln840Pro	missense	Exon 7 of 9	ENSP00000319248.9	P37275-1
ZEB1	ENST00000437844.6	TSL:1	n.*2659A>C		non_coding_transcript_exon	Exon 9 of 11	ENSP00000405958.3	F6U0D0

Frequencies

GnomAD3 genomes

AF:

0.00651

AC:

990

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0351

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00744

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00744

AC:

1864

AN:

250532

AF XY:

0.00752

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0335

Gnomad NFE exome

AF:

0.00773

Gnomad OTH exome

AF:

0.00786

GnomAD4 exome

AF:

0.00721

AC:

10531

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00713

AC XY:

5187

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

33452

American (AMR)

AF:

0.00255

AC:

114

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00391

AC:

337

AN:

86236

European-Finnish (FIN)

AF:

0.0324

AC:

1731

AN:

53408

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00718

AC:

7986

AN:

1111876

Other (OTH)

AF:

0.00543

AC:

328

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

659

1318

1976

2635

3294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00650

AC:

990

AN:

152288

Hom.:

Cov.:

AF XY:

0.00788

AC XY:

587

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

41572

American (AMR)

AF:

0.00294

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0351

AC:

372

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00744

AC:

506

AN:

68028

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00659

Hom.:

Bravo

AF:

0.00396

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00725

AC:

880

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00700

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Corneal dystrophy, Fuchs endothelial, 6 (3)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0085

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

7.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.33

Sift

Benign

0.037

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.87

MVP

0.59

MPC

0.49

ClinPred

0.012

GERP RS

5.7

Varity_R

0.28

gMVP

0.53

Mutation Taster

=9/91

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over