chr1-244055155-AAC-TCT

Variant names:

• chr1-244055155-AAC-TCT
• NM_205768.3:c.1381_1383delAACinsTCT
• ZBTB18 p.Asn461Ser

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2

The NM_205768.3(ZBTB18):c.1381_1383delAACinsTCT (p.Asn461Ser) variant causes a missense change. 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: 9.32). 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: 9.32
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 9 pathogenic, 0 benign (OR vs. background: 95.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

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.1381_1383delAACinsTCT p.Asn461Ser	missense	N/A	Prot: NP_991331.1 UniProt:
	ZBTB18 NM_001278196.2		c.1354_1356delAACinsTCT p.Asn452Ser	missense	N/A	Prot: NP_001265125.1 UniProt:
	ZBTB18 NM_006352.5		c.1354_1356delAACinsTCT p.Asn452Ser	missense	N/A	Prot: NP_006343.2

ZBTB18 NM_205768.3

MANE Select

HGVSc / HGVSpc.1381_1383delAACinsTCTp.Asn461Ser

Exon rankN/A

missense

Prot: NP_991331.1UniProt: Q99592-2

ZBTB18 NM_001278196.2

HGVSc / HGVSpc.1354_1356delAACinsTCTp.Asn452Ser

Exon rankN/A

missense

Prot: NP_001265125.1UniProt: Q99592-1

ZBTB18 NM_006352.5

HGVSc / HGVSpc.1354_1356delAACinsTCTp.Asn452Ser

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.1381_1383delAACinsTCT p.Asn461Ser	missense	N/A	Prot: ENSP00000351539.4 UniProt:
	ZBTB18 ENST00000914124.1		c.1381_1383delAACinsTCT p.Asn461Ser	missense	N/A	Prot: ENSP00000584183.1 UniProt:
	ZBTB18 ENST00000622512.1	TSL:3	c.1354_1356delAACinsTCT p.Asn452Ser	missense	N/A	Prot: ENSP00000481278.1 UniProt:

ZBTB18 ENST00000358704.4

TSL:1MANE Select

HGVSc / HGVSpc.1381_1383delAACinsTCTp.Asn461Ser

Exon rankN/A

missense

Prot: ENSP00000351539.4UniProt: Q99592-2

ZBTB18 ENST00000914124.1

HGVSc / HGVSpc.1381_1383delAACinsTCTp.Asn461Ser

Exon rankN/A

missense

Prot: ENSP00000584183.1UniProt: Q99592-2

ZBTB18 ENST00000622512.1

TSL:3

HGVSc / HGVSpc.1354_1356delAACinsTCTp.Asn452Ser

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	Pathogenic	9.3

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: chr1-244218457;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar