rs879255635

Variant names:

• chr3-114339384-G-A
• rs879255635
• NM_001348800.3:c.1847C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001348800.3(ZBTB20):​c.1847C>T​(p.Ser616Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB20 NM_001348800.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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 9 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 the ZBTB20 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 4.272 (above the threshold of 3.09). Trascript score misZ: 3.9474 (above the threshold of 3.09). GenCC associations: The gene is linked to Primrose syndrome, diabetes mellitus.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 3-114339384-G-A is Pathogenic according to our data. Variant chr3-114339384-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 264659.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-114339384-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB20	NM_001348800.3	c.1847C>T	p.Ser616Phe	missense_variant	Exon 12 of 12	ENST00000675478.1	NP_001335729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB20	ENST00000675478.1	c.1847C>T	p.Ser616Phe	missense_variant	Exon 12 of 12		NM_001348800.3	ENSP00000501561.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 13, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27061120, 32266967) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;.;.;.;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;.;T;.;.;D;.
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	.;.;.;.;.;M;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.014	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;.
Vest4		0.86
MutPred		0.74		.;.;.;.;.;Loss of loop (P = 0.0804);.;
MVP		0.41
MPC		2.5
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.70
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs879255635; hg19: chr3-114058231; COSMIC: COSV61862279;