rs1553270522

Variant names:

• chr1-244054803-TGATGA-T
• rs1553270522
• NM_205768.3:c.1035_1039delGATGA

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). PVS1PM2PP5_Moderate

The NM_205768.3(ZBTB18):c.1035_1039delGATGA (p.Glu345AspfsTer154) variant causes a frameshift change. This is a loss-of-function variant that does not trigger NMD. 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: 9.33). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.33
• 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
	PVS1Null variant in LOF gene		Non-NMD frameshift: ≥4 downstream pathogenic — very strong evidence preserved (PVS1); Frameshift (exon 2 of 2) at amino acid 345 of 531; NMD not predicted. 46 pathogenic variants downstream support preserved loss-of-function impact. A new stop codon is introduced in the shifted frame, truncating the protein to ~497 amino acids (34 amino acids lost).
	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.
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

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.1035_1039delGATGA p.Glu345AspfsTer154	frameshift	Exon 2 of 2	Prot: NP_991331.1 UniProt:
	ZBTB18 NM_001278196.2		c.1008_1012delGATGA p.Glu336AspfsTer154	frameshift	Exon 2 of 2	Prot: NP_001265125.1 UniProt:
	ZBTB18 NM_006352.5		c.1008_1012delGATGA p.Glu336AspfsTer154	frameshift	Exon 1 of 1	Prot: NP_006343.2

ZBTB18 NM_205768.3

MANE Select

HGVSc / HGVSpc.1035_1039delGATGAp.Glu345AspfsTer154

Exon rankExon 2 of 2

frameshift

Prot: NP_991331.1UniProt: Q99592-2

ZBTB18 NM_001278196.2

HGVSc / HGVSpc.1008_1012delGATGAp.Glu336AspfsTer154

Exon rankExon 2 of 2

frameshift

Prot: NP_001265125.1UniProt: Q99592-1

ZBTB18 NM_006352.5

HGVSc / HGVSpc.1008_1012delGATGAp.Glu336AspfsTer154

Exon rankExon 1 of 1

frameshift

Prot: NP_006343.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ZBTB18 ENST00000358704.4	TSL:1MANE Select	c.1035_1039delGATGA p.Glu345AspfsTer154	frameshift	Exon 2 of 2	Prot: ENSP00000351539.4 UniProt:
	ZBTB18 ENST00000914124.1		c.1035_1039delGATGA p.Glu345AspfsTer154	frameshift	Exon 3 of 3	Prot: ENSP00000584183.1 UniProt:
	ZBTB18 ENST00000622512.1	TSL:3	c.1008_1012delGATGA p.Glu336AspfsTer154	frameshift	Exon 2 of 2	Prot: ENSP00000481278.1 UniProt:

ZBTB18 ENST00000358704.4

TSL:1MANE Select

HGVSc / HGVSpc.1035_1039delGATGAp.Glu345AspfsTer154

Exon rankExon 2 of 2

frameshift

Prot: ENSP00000351539.4UniProt: Q99592-2

ZBTB18 ENST00000914124.1

HGVSc / HGVSpc.1035_1039delGATGAp.Glu345AspfsTer154

Exon rankExon 3 of 3

frameshift

Prot: ENSP00000584183.1UniProt: Q99592-2

ZBTB18 ENST00000622512.1

TSL:3

HGVSc / HGVSpc.1008_1012delGATGAp.Glu336AspfsTer154

Exon rankExon 2 of 2

frameshift

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

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	10/190	disease causing (ClinVar)
PhyloP100	Pathogenic	9.3

Showing 2 of 2 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

dbSNP: rs1553270522;

hg19: chr1-244218105;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar