chr1-244053916-C-G

Position:

• chr1-244053916-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_205768.3(ZBTB18):​c.142C>G​(p.Arg48Gly) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 3.94

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 domain BTB (size 67) in uniprot entity ZBT18_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 1-244053916-C-G is Pathogenic according to our data. Variant chr1-244053916-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1311575.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB18	NM_205768.3	c.142C>G	p.Arg48Gly	missense_variant	2/2	ENST00000358704.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB18	ENST00000358704.4	c.142C>G	p.Arg48Gly	missense_variant	2/2	1	NM_205768.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 22 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	May 05, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	Mar 09, 2022	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.9	.;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.83		Loss of methylation at R39 (P = 0.0496);.;
MVP		0.85
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.80
gMVP		0.98

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: rs1135401770; hg19: chr1-244217218;