rs797044885

Variant names:

• chr1-244055156-A-G
• rs797044885
• NM_205768.3:c.1382A>G
• ZBTB18 p.Asn461Ser

Your query was ambiguous. Multiple possible variants found:

• chr1-244055156-A-G
• chr1-244055156-A-C

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). PS3PM1PM2PP5_Strong

The NM_205768.3(ZBTB18):c.1382A>G (p.Asn461Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.30). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005325448: Published functional studies demonstrate a damaging effect with impaired transcriptional repression (Hemming et al., 2019);".

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.29
• Publications: 3 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
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV005325448: Published functional studies demonstrate a damaging effect with impaired transcriptional repression (Hemming et al., 2019);
	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.
	PP5Reputable source reports pathogenic		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.1382A>G p.Asn461Ser	missense	Exon 2 of 2	Prot: NP_991331.1 UniProt:
	ZBTB18 NM_001278196.2		c.1355A>G p.Asn452Ser	missense	Exon 2 of 2	Prot: NP_001265125.1 UniProt:
	ZBTB18 NM_006352.5		c.1355A>G p.Asn452Ser	missense	Exon 1 of 1	Prot: NP_006343.2

ZBTB18 NM_205768.3

MANE Select

HGVSc / HGVSpc.1382A>Gp.Asn461Ser

Exon rankExon 2 of 2

missense

Prot: NP_991331.1UniProt: Q99592-2

ZBTB18 NM_001278196.2

HGVSc / HGVSpc.1355A>Gp.Asn452Ser

Exon rankExon 2 of 2

missense

Prot: NP_001265125.1UniProt: Q99592-1

ZBTB18 NM_006352.5

HGVSc / HGVSpc.1355A>Gp.Asn452Ser

Exon rankExon 1 of 1

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.1382A>G p.Asn461Ser	missense	Exon 2 of 2	Prot: ENSP00000351539.4 UniProt:
	ZBTB18 ENST00000914124.1		c.1382A>G p.Asn461Ser	missense	Exon 3 of 3	Prot: ENSP00000584183.1 UniProt:
	ZBTB18 ENST00000622512.1	TSL:3	c.1355A>G p.Asn452Ser	missense	Exon 2 of 2	Prot: ENSP00000481278.1 UniProt:

ZBTB18 ENST00000358704.4

TSL:1MANE Select

HGVSc / HGVSpc.1382A>Gp.Asn461Ser

Exon rankExon 2 of 2

missense

Prot: ENSP00000351539.4UniProt: Q99592-2

ZBTB18 ENST00000914124.1

HGVSc / HGVSpc.1382A>Gp.Asn461Ser

Exon rankExon 3 of 3

missense

Prot: ENSP00000584183.1UniProt: Q99592-2

ZBTB18 ENST00000622512.1

TSL:3

HGVSc / HGVSpc.1355A>Gp.Asn452Ser

Exon rankExon 2 of 2

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:187104	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-9.4
GPN-Star score	N/A	9.4
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.86	T
Mutation Taster	N/A	17/83	disease causing (ClinVar)
MutationAssessor	Benign	0.080	N
PhyloP100	Uncertain	7.3
popEVE	Benign	-3.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.021	D
Varity_R	N/A	0.39
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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: rs797044885;

hg19: chr1-244218458;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar