rs875989786

Variant names:

• chr1-244054957-C-T
• rs875989786
• NM_205768.3:c.1183C>T
• ZBTB18 p.Gln395*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_205768.3(ZBTB18):c.1183C>T (p.Gln395*) variant causes a stop gained change involving the alteration of a conserved nucleotide. This is a loss-of-function variant that does not trigger NMD. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (addAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.91
• Publications: 2 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina, G2P

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 14 points.

• PVS1: Non-NMD frameshift: ≥4 downstream pathogenic — very strong evidence preserved (PVS1); Stop-gained (exon 2 of 2) at amino acid 395 of 531; NMD not predicted. 39 pathogenic variants downstream support preserved loss-of-function impact.
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 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.1183C>T	p.Gln395*	stop_gained	Exon 2 of 2	NP_991331.1	Q99592-2
	ZBTB18	NM_001278196.2		c.1156C>T	p.Gln386*	stop_gained	Exon 2 of 2	NP_001265125.1	Q99592-1
	ZBTB18	NM_006352.5		c.1156C>T	p.Gln386*	stop_gained	Exon 1 of 1	NP_006343.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB18	ENST00000358704.4	TSL:1 MANE Select	c.1183C>T	p.Gln395*	stop_gained	Exon 2 of 2	ENSP00000351539.4	Q99592-2
	ZBTB18	ENST00000914124.1		c.1183C>T	p.Gln395*	stop_gained	Exon 3 of 3	ENSP00000584183.1
	ZBTB18	ENST00000622512.1	TSL:3	c.1156C>T	p.Gln386*	stop_gained	Exon 2 of 2	ENSP00000481278.1	Q99592-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability, autosomal dominant 22 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		7.9
Mutation Taster		=0/200	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs875989786;

hg19: chr1-244218259;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar