NM_205768.3:c.307A>G

Variant names:

• chr1-244054081-A-G
• rs1057520130
• NM_205768.3:c.307A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 16/22 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
• Publications: 0 publications found

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]

ZBTB18 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 22

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047216356).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_205768.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB18	NM_205768.3	MANE Select	c.307A>G	p.Ile103Val	missense	Exon 2 of 2	NP_991331.1	Q99592-2
	ZBTB18	NM_001278196.2		c.280A>G	p.Ile94Val	missense	Exon 2 of 2	NP_001265125.1	Q99592-1
	ZBTB18	NM_006352.5		c.280A>G	p.Ile94Val	missense	Exon 1 of 1	NP_006343.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB18	ENST00000358704.4	TSL:1 MANE Select	c.307A>G	p.Ile103Val	missense	Exon 2 of 2	ENSP00000351539.4	Q99592-2
	ZBTB18	ENST00000914124.1		c.307A>G	p.Ile103Val	missense	Exon 3 of 3	ENSP00000584183.1
	ZBTB18	ENST00000622512.1	TSL:3	c.280A>G	p.Ile94Val	missense	Exon 2 of 2	ENSP00000481278.1	Q99592-1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.2	N
PhyloP100		5.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1057520130; hg19: chr1-244217383;