1-244055156-A-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_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 was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_205768.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ZBTB18 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 3.4305 (above the threshold of 3.09). Trascript score misZ: 4.2468 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 22, complex neurodevelopmental disorder.
• PP5: Variant 1-244055156-A-G is Pathogenic according to our data. Variant chr1-244055156-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 208690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-244055156-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB18	NM_205768.3	c.1382A>G	p.Asn461Ser	missense_variant	Exon 2 of 2	ENST00000358704.4	NP_991331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB18	ENST00000358704.4	c.1382A>G	p.Asn461Ser	missense_variant	Exon 2 of 2	1	NM_205768.3	ENSP00000351539.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jun 01, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with impaired transcriptional repression (Hemming et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27513193, 35083747, 37525067, 32959890, 27598823, 28345786, 25131622, 28688840, 31112317) -

Intellectual disability Pathogenic:1

Jul 20, 2020

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

de novo missense variant preiously reported, affecting the ZF domain. -

Intellectual disability, autosomal dominant 22 Pathogenic:1

Apr 05, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.080	N;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.9	.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	.;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.99	D;D
Vest4		0.77
MutPred		0.57		Gain of disorder (P = 0.0368);.;
MVP		0.39
MPC		1.6
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.39
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044885; hg19: chr1-244218458;