chr1-244055164-C-T

Variant names:

• chr1-244055164-C-T
• rs750922282
• NM_205768.3:c.1390C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_205768.3(ZBTB18):​c.1390C>T​(p.Arg464Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R464P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.91

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 10 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, 4 uncertain in NM_205768.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-244055165-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 617452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826
• PP5: Variant 1-244055164-C-T is Pathogenic according to our data. Variant chr1-244055164-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 440857.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB18	NM_205768.3	c.1390C>T	p.Arg464Cys	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.1390C>T	p.Arg464Cys	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:3

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 22 Pathogenic:2

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 05, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Dec 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27598823) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.5	.;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.66		Loss of MoRF binding (P = 0.0094);.;
MVP		0.69
MPC		2.2
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.53
gMVP		0.90

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: rs750922282; hg19: chr1-244218466; COSMIC: COSV100699998;