rs1057520130

chr1-244054081-A-Gchr1-244054081-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_205768.3(ZBTB18):c.307A>G(p.Ile103Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. I103F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ZBTB18 NM_205768.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ZBTB18
• BP4: Computational evidence support a benign effect (MetaRNN=0.047216356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB18	NM_205768.3	c.307A>G	p.Ile103Val	missense_variant	2/2	ENST00000358704.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB18	ENST00000358704.4	c.307A>G	p.Ile103Val	missense_variant	2/2	1	NM_205768.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2023

The c.307A>G (p.I103V) alteration is located in exon 2 (coding exon 2) of the ZBTB18 gene. This alteration results from a A to G substitution at nucleotide position 307, causing the isoleucine (I) at amino acid position 103 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	21
Dann	Benign	0.58
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.2	N;.
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.40	T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.51		Gain of ubiquitination at K90 (P = 0.1446);.;
MVP		0.23
MPC		0.70
ClinPred		0.81	D
GERP RS		3.9
Varity_R		0.083
gMVP		0.48

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: rs1057520130; hg19: chr1-244217383;