chr3-114339362-C-G

Variant names:

• chr3-114339362-C-G
• rs1553789275
• NM_001348800.3:c.1869G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001348800.3(ZBTB20):​c.1869G>C​(p.Lys623Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB20 NM_001348800.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.81
• Publications: 2 publications found

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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp, Ambry Genetics
• diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 12 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
• PP5: Variant 3-114339362-C-G is Pathogenic according to our data. Variant chr3-114339362-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 520946.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB20	NM_001348800.3	MANE Select	c.1869G>C	p.Lys623Asn	missense	Exon 12 of 12	NP_001335729.1	Q9HC78-1
	ZBTB20	NM_001164342.2		c.1869G>C	p.Lys623Asn	missense	Exon 5 of 5	NP_001157814.1	Q9HC78-1
	ZBTB20	NM_001348803.3		c.1869G>C	p.Lys623Asn	missense	Exon 14 of 14	NP_001335732.1	Q9HC78-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB20	ENST00000675478.1	MANE Select	c.1869G>C	p.Lys623Asn	missense	Exon 12 of 12	ENSP00000501561.1	Q9HC78-1
	ZBTB20	ENST00000474710.6	TSL:1	c.1869G>C	p.Lys623Asn	missense	Exon 14 of 14	ENSP00000419153.1	Q9HC78-1
	ZBTB20	ENST00000357258.8	TSL:1	c.1650G>C	p.Lys550Asn	missense	Exon 10 of 10	ENSP00000349803.3	Q9HC78-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0097	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.14
Sift	Benign	0.034	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.57	P
Vest4		0.39
MutPred		0.63		Loss of methylation at K623 (P = 0.0475)
MVP		0.45
MPC		2.5
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.43
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553789275; hg19: chr3-114058209;