chr9-126879887-ACC-A

Position:

• chr9-126879887-ACC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001099270.4(ZBTB34):​c.490_491delCC​(p.Pro164fs) variant causes a frameshift 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB34 NM_001099270.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

Genes affected

ZBTB34 (HGNC:31446): (zinc finger and BTB domain containing 34) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.677 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB34	NM_001099270.4	c.490_491delCC	p.Pro164fs	frameshift_variant	2/2	ENST00000319119.5	NP_001092740.2
ZBTB34	NM_001395198.1	c.520_521delCC	p.Pro174fs	frameshift_variant	3/3		NP_001382127.1
ZBTB34	XM_047423402.1	c.520_521delCC	p.Pro174fs	frameshift_variant	3/3		XP_047279358.1
ZBTB34	XM_011518699.4	c.490_491delCC	p.Pro164fs	frameshift_variant	2/2		XP_011517001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB34	ENST00000319119.5	c.490_491delCC	p.Pro164fs	frameshift_variant	2/2	1	NM_001099270.4	ENSP00000317534.4
ZBTB34	ENST00000695642.1	c.520_521delCC	p.Pro174fs	frameshift_variant	3/3			ENSP00000512077.1

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jun 19, 2024

The heterozygous p.Pro164SerfsTer19 variant in ZBTB34 was identified by our study in 1 individual with a neurodevelopmental disorder. While this gene is still lacking sufficient evidence to establish a gene-disease relationship, we believe this is a possible novel gene candidate for neurodevelopmental disorders. Given the limited information about this gene-disease relationship, the significance of the p.Pro164SerfsTer19 variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in ZBTB34 we encourage you to reach out to us. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-129642166;