rs797044885

Variant names:

• chr1-244055156-A-C
• rs797044885
• NM_205768.3:c.1382A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-244055156-A-C
• chr1-244055156-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_205768.3(ZBTB18):​c.1382A>C​(p.Asn461Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N461S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29

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_pathogenic. Variant got 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, 2 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 chr1-244055156-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 208690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the ZBTB18 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 3.4305 (above the threshold of 3.09). Trascript score misZ: 4.2468 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 22, complex neurodevelopmental disorder.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB18	NM_205768.3	c.1382A>C	p.Asn461Thr	missense_variant	Exon 2 of 2	ENST00000358704.4	NP_991331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB18	ENST00000358704.4	c.1382A>C	p.Asn461Thr	missense_variant	Exon 2 of 2	1	NM_205768.3	ENSP00000351539.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.5	.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.018	.;D
Sift4G	Benign	0.10	T;T
Polyphen		0.99	D;D
Vest4		0.38
MutPred		0.56		Gain of disorder (P = 0.1157);.;
MVP		0.19
MPC		1.9
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.93

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: rs797044885; hg19: chr1-244218458;