Genetic Variant ZEB1:c.259+5693C>G (chr10-31466930-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001174096.2(ZEB1):c.259+5693C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 152,052 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.015 ( 53 hom., cov: 32)

Consequence

ZEB1
NM_001174096.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.805

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0151 (2291/152052) while in subpopulation AFR AF = 0.0508 (2105/41464). AF 95% confidence interval is 0.049. There are 53 homozygotes in GnomAd4. There are 1093 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2291 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB1	NM_001174096.2 link	c.259+5693C>G		intron_variant	Intron 2 of 8	ENST00000424869.6	NP_001167567.1	P37275-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB1	ENST00000424869.6 link	c.259+5693C>G		intron_variant	Intron 2 of 8	5	NM_001174096.2	ENSP00000415961.2		P37275-2F6TDF5

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2286

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00721

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.0172

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0151

AC:

2291

AN:

152052

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1093

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0508

AC:

2105

AN:

41464

American (AMR)

AF:

0.00720

AC:

110

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000208

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

67978

Other (OTH)

AF:

0.0171

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

111

221

332

442

553

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0113

Hom.:

Bravo

AF:

0.0175

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.89

(source)

DANN

Benign

0.80

PhyloP100

-0.81

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over