rs1085307108

Variant names:

• chr1-244054716-CAG-C
• rs1085307108
• NM_205768.3:c.943_944delAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_205768.3(ZBTB18):​c.943_944delAG​(p.Arg315GlyfsTer4) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.47

Genes affected

ZBTB18 (HGNC:13030): (zinc finger and BTB domain containing 18) This gene encodes a C2H2-type zinc finger protein which acts a transcriptional repressor of genes involved in neuronal development. The encoded protein recognizes a specific sequence motif and recruits components of chromatin to target genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 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. There are 41 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-244054716-CAG-C is Pathogenic according to our data. Variant chr1-244054716-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 225922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB18	NM_205768.3	c.943_944delAG	p.Arg315GlyfsTer4	frameshift_variant	Exon 2 of 2	ENST00000358704.4	NP_991331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB18	ENST00000358704.4	c.943_944delAG	p.Arg315GlyfsTer4	frameshift_variant	Exon 2 of 2	1	NM_205768.3	ENSP00000351539.4

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: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 22 Pathogenic:2

Apr 05, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 23, 2020

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Apr 28, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.943_944delAG variant in the ZBTB18 gene has been observed in internal GeneDx whole exome sequencing data in association with developmental delay, severely limited speech, microcephaly, and hypoplasia of the corpus callosum. The c.943_944delAG variant causes a frameshift starting with codon Arginine 315, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Arg315GlyfsX4. This variant is predicted to cause loss of normal protein function through protein truncation. The c.943_944delAG variant causes the typical last 217 amino acids to be deleted and replaced by three alternate amino acids. The c.943_944delAG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.943_944delAG as a pathogenic variant. -

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

LitVar

Other links and lift over

dbSNP: rs1085307108; hg19: chr1-244218018;