1-244055156-A-G

Position:

• chr1-244055156-A-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 gene, where missense usually causes diseases (based on misZ statistic), ZBTB18. . Gene score misZ 3.4305 (greater than the threshold 3.09). Trascript score misZ 4.2468 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
ZBTB18	NM_205768.3	c.1382A>G	p.Asn461Ser	missense_variant	2/2	ENST00000358704.4	NP_991331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB18	ENST00000358704.4	c.1382A>G	p.Asn461Ser	missense_variant	2/2	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Jul 20, 2020

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

Intellectual disability, autosomal dominant 22 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 05, 2022

- -

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;