NM_205768.3:c.170A>T

Variant names:

• chr1-244053944-A-T
• NM_205768.3:c.170A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_205768.3(ZBTB18):​c.170A>T​(p.Tyr57Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZBTB18 NM_205768.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.170A>T	p.Tyr57Phe	missense	Exon 2 of 2	NP_991331.1	Q99592-2
	ZBTB18	NM_001278196.2		c.143A>T	p.Tyr48Phe	missense	Exon 2 of 2	NP_001265125.1	Q99592-1
	ZBTB18	NM_006352.5		c.143A>T	p.Tyr48Phe	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.170A>T	p.Tyr57Phe	missense	Exon 2 of 2	ENSP00000351539.4	Q99592-2
	ZBTB18	ENST00000914124.1		c.170A>T	p.Tyr57Phe	missense	Exon 3 of 3	ENSP00000584183.1
	ZBTB18	ENST00000622512.1	TSL:3	c.143A>T	p.Tyr48Phe	missense	Exon 2 of 2	ENSP00000481278.1	Q99592-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.35	N
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.46
Sift	Benign	0.40	T
Sift4G	Benign	0.60	T
Polyphen		0.24	B
Vest4		0.61
MutPred		0.90		Gain of MoRF binding (P = 0.3873)
MVP		0.60
MPC		1.8
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.41
gMVP		0.87
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

hg19: chr1-244217246;