rs483353070

Positions:

• chr3-114339370-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001348800.3(ZBTB20):​c.1861C>T​(p.Leu621Phe) variant causes a missense change. 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: 32)
• Consequence: ZBTB20 NM_001348800.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.71

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a zinc_finger_region C2H2-type 2 (size 22) in uniprot entity ZBT20_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001348800.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZBTB20. . Gene score misZ 4.272 (greater than the threshold 3.09). Trascript score misZ 3.9474 (greater than threshold 3.09). GenCC has associacion of gene with Primrose syndrome, diabetes mellitus.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 3-114339370-G-A is Pathogenic according to our data. Variant chr3-114339370-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 139449.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-114339370-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB20	NM_001348800.3	c.1861C>T	p.Leu621Phe	missense_variant	12/12	ENST00000675478.1	NP_001335729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB20	ENST00000675478.1	c.1861C>T	p.Leu621Phe	missense_variant	12/12		NM_001348800.3	ENSP00000501561	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Primrose syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;.;.;.;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	.;.;T;.;.;T;.
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.8	.;.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.037	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;.
Vest4		0.90
MutPred		0.79		.;.;.;.;.;Gain of methylation at K623 (P = 0.1144);.;
MVP		0.72
MPC		2.4
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.52
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs483353070; hg19: chr3-114058217;