Genetic Variant ZBTB18:p.Arg464Ser (chr1-244055164-C-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_205768.3(ZBTB18):c.1390C>A(p.Arg464Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R464P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ZBTB18
NM_205768.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

2 publications found

Variant links:

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)

ZBTB18 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 6 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-244055165-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 975781.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.777

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZBTB18	NM_205768.3	MANE Select	c.1390C>A	p.Arg464Ser	missense	Exon 2 of 2	NP_991331.1	Q99592-2
ZBTB18	NM_001278196.2		c.1363C>A	p.Arg455Ser	missense	Exon 2 of 2	NP_001265125.1	Q99592-1
ZBTB18	NM_006352.5		c.1363C>A	p.Arg455Ser	missense	Exon 1 of 1	NP_006343.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZBTB18	ENST00000358704.4	TSL:1 MANE Select	c.1390C>A	p.Arg464Ser	missense	Exon 2 of 2	ENSP00000351539.4	Q99592-2
ZBTB18	ENST00000914124.1		c.1390C>A	p.Arg464Ser	missense	Exon 3 of 3	ENSP00000584183.1
ZBTB18	ENST00000622512.1	TSL:3	c.1363C>A	p.Arg455Ser	missense	Exon 2 of 2	ENSP00000481278.1	Q99592-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

PhyloP100

7.9

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.44

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MutPred

0.69

Loss of MoRF binding (P = 0.0199)

MVP

0.63

MPC

1.9

ClinPred

0.97

GERP RS

5.8

Varity_R

0.75

gMVP

0.94

Mutation Taster

=5/95

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over