rs1553270640

Variant names:

• chr1-244055267-A-C
• rs1553270640
• NM_205768.3:c.1493A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-244055267-A-C
• chr1-244055267-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_205768.3(ZBTB18):​c.1493A>C​(p.His498Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H498R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_205768.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 1-244055267-A-C is Pathogenic according to our data. Variant chr1-244055267-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 545593.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1493A>C	p.His498Pro	missense	Exon 2 of 2	NP_991331.1	Q99592-2
	ZBTB18	NM_001278196.2		c.1466A>C	p.His489Pro	missense	Exon 2 of 2	NP_001265125.1	Q99592-1
	ZBTB18	NM_006352.5		c.1466A>C	p.His489Pro	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.1493A>C	p.His498Pro	missense	Exon 2 of 2	ENSP00000351539.4	Q99592-2
	ZBTB18	ENST00000914124.1		c.1493A>C	p.His498Pro	missense	Exon 3 of 3	ENSP00000584183.1
	ZBTB18	ENST00000622512.1	TSL:3	c.1466A>C	p.His489Pro	missense	Exon 2 of 2	ENSP00000481278.1	Q99592-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, autosomal dominant 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.80		Loss of catalytic residue at E491 (P = 0.0482)
MVP		0.68
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.69
gMVP		1.0
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs1553270640; hg19: chr1-244218569;