Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The NM_001348800.3(ZBTB20):c.1768A>C(p.Lys590Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K590E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

ZBTB20
NM_001348800.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.67

Publications

4 publications found

Variant links:

Genes affected

ZBTB20 (HGNC:13503): (zinc finger and BTB domain containing 20) This gene, which was initially designated as dendritic cell-derived BTB/POZ zinc finger (DPZF), belongs to a family of transcription factors with an N-terminal BTB/POZ domain and a C-terminal DNA-bindng zinc finger domain. The BTB/POZ domain is a hydrophobic region of approximately 120 aa which mediates association with other BTB/POZ domain-containing proteins. This gene acts as a transcriptional repressor and plays a role in many processes including neurogenesis, glucose homeostasis, and postnatal growth. Mutations in this gene have been associated with Primrose syndrome as well as the 3q13.31 microdeletion syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

ZBTB20 Gene-Disease associations (from GenCC):

Primrose syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ZBTB20 links:

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ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001348800.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-114350310-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3472130.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 3-114350310-T-G is Pathogenic according to our data. Variant chr3-114350310-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 139436.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348800.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZBTB20	NM_001348800.3	MANE Select	c.1768A>C	p.Lys590Gln	missense	Exon 11 of 12	NP_001335729.1
ZBTB20	NM_001164342.2		c.1768A>C	p.Lys590Gln	missense	Exon 4 of 5	NP_001157814.1
ZBTB20	NM_001348803.3		c.1768A>C	p.Lys590Gln	missense	Exon 13 of 14	NP_001335732.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZBTB20	ENST00000675478.1	MANE Select	c.1768A>C	p.Lys590Gln	missense	Exon 11 of 12	ENSP00000501561.1
ZBTB20	ENST00000474710.6	TSL:1	c.1768A>C	p.Lys590Gln	missense	Exon 13 of 14	ENSP00000419153.1
ZBTB20	ENST00000357258.8	TSL:1	c.1549A>C	p.Lys517Gln	missense	Exon 9 of 10	ENSP00000349803.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primrose syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

PhyloP100

7.7

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.43

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.022

Polyphen

1.0

Vest4

0.77

MutPred

0.55

Loss of methylation at K590 (P = 0.0112)

MVP

0.47

MPC

2.4

ClinPred

0.97

GERP RS

6.0

Varity_R

0.70

gMVP

0.81

Mutation Taster

=0/100

disease causing (ClinVar)

(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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rs483353064

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over