1-244053805-G-C

Position:

• chr1-244053805-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_205768.3(ZBTB18):​c.31G>C​(p.Glu11Gln) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E11V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-244053806-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2429450.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB18	NM_205768.3	c.31G>C	p.Glu11Gln	missense_variant	2/2	ENST00000358704.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB18	ENST00000358704.4	c.31G>C	p.Glu11Gln	missense_variant	2/2	1	NM_205768.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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	Benign	0.33
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	.;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.71
MutPred		0.31		Loss of phosphorylation at S7 (P = 0.201);.;
MVP		0.58
MPC		1.9
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.44
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-244217107;