1-244055156-AC-CA

Variant names:

• chr1-244055156-AC-CA
• NM_205768.3:c.1382_1383delACinsCA
• ZBTB18 p.Asn461Thr

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_Supporting

The NM_205768.3(ZBTB18):c.1382_1383delACinsCA (p.Asn461Thr) variant causes a missense change. The gene ZBTB18 is a tumor suppressor gene (CancerMine: 4 TSG citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.30). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29
• Publications: 0 publications found

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]

ZBTB18 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 22

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae)

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 9 pathogenic, 0 benign (OR vs. background: 95.0); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_205768.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ZBTB18 NM_205768.3	MANE Select	c.1382_1383delACinsCA p.Asn461Thr	missense	N/A	Prot: NP_991331.1 UniProt:
	ZBTB18 NM_001278196.2		c.1355_1356delACinsCA p.Asn452Thr	missense	N/A	Prot: NP_001265125.1 UniProt:
	ZBTB18 NM_006352.5		c.1355_1356delACinsCA p.Asn452Thr	missense	N/A	Prot: NP_006343.2

ZBTB18 NM_205768.3

MANE Select

HGVSc / HGVSpc.1382_1383delACinsCAp.Asn461Thr

Exon rankN/A

missense

Prot: NP_991331.1UniProt: Q99592-2

ZBTB18 NM_001278196.2

HGVSc / HGVSpc.1355_1356delACinsCAp.Asn452Thr

Exon rankN/A

missense

Prot: NP_001265125.1UniProt: Q99592-1

ZBTB18 NM_006352.5

HGVSc / HGVSpc.1355_1356delACinsCAp.Asn452Thr

Exon rankN/A

missense

Prot: NP_006343.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ZBTB18 ENST00000358704.4	TSL:1MANE Select	c.1382_1383delACinsCA p.Asn461Thr	missense	N/A	Prot: ENSP00000351539.4 UniProt:
	ZBTB18 ENST00000914124.1		c.1382_1383delACinsCA p.Asn461Thr	missense	N/A	Prot: ENSP00000584183.1 UniProt:
	ZBTB18 ENST00000622512.1	TSL:3	c.1355_1356delACinsCA p.Asn452Thr	missense	N/A	Prot: ENSP00000481278.1 UniProt:

ZBTB18 ENST00000358704.4

TSL:1MANE Select

HGVSc / HGVSpc.1382_1383delACinsCAp.Asn461Thr

Exon rankN/A

missense

Prot: ENSP00000351539.4UniProt: Q99592-2

ZBTB18 ENST00000914124.1

HGVSc / HGVSpc.1382_1383delACinsCAp.Asn461Thr

Exon rankN/A

missense

Prot: ENSP00000584183.1UniProt: Q99592-2

ZBTB18 ENST00000622512.1

TSL:3

HGVSc / HGVSpc.1355_1356delACinsCAp.Asn452Thr

Exon rankN/A

missense

Prot: ENSP00000481278.1UniProt: Q99592-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	7.3

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr1-244218458;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar