3-114339368-AAG-GAA

Variant names:

• chr3-114339368-AAG-GAA
• NM_001348800.3:c.1861_1863delCTTinsTTC
• ZBTB20 p.Leu621Phe

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1 PM1 PM5 PP3

The NM_001348800.3(ZBTB20):​c.1861_1863delCTTinsTTC​(p.Leu621Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L621R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB20 NM_001348800.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 0 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• diabetes mellitus

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_001348800.3 (ZBTB20) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001348800.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-114339369-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2627841.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1861_1863delCTTinsTTC	p.Leu621Phe	missense	N/A	NP_001335729.1	Q9HC78-1
	ZBTB20	NM_001164342.2		c.1861_1863delCTTinsTTC	p.Leu621Phe	missense	N/A	NP_001157814.1	Q9HC78-1
	ZBTB20	NM_001348803.3		c.1861_1863delCTTinsTTC	p.Leu621Phe	missense	N/A	NP_001335732.1	Q9HC78-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB20	ENST00000675478.1	MANE Select	c.1861_1863delCTTinsTTC	p.Leu621Phe	missense	N/A	ENSP00000501561.1	Q9HC78-1
	ZBTB20	ENST00000474710.6	TSL:1	c.1861_1863delCTTinsTTC	p.Leu621Phe	missense	N/A	ENSP00000419153.1	Q9HC78-1
	ZBTB20	ENST00000357258.8	TSL:1	c.1642_1644delCTTinsTTC	p.Leu548Phe	missense	N/A	ENSP00000349803.3	Q9HC78-2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-114058215;