rs1064793829

Positions:

• chr1-153816570-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020699.4(GATAD2B):​c.918del​(p.Pro307HisfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATAD2B NM_020699.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.214

Genes affected

GATAD2B (HGNC:30778): (GATA zinc finger domain containing 2B) This gene encodes a zinc finger protein transcriptional repressor. The encoded protein is part of the methyl-CpG-binding protein-1 complex, which represses gene expression by deacetylating methylated nucleosomes. Mutations in this gene are linked to intellectual disability and dysmorphic features associated with cognitive disability. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-153816570-GA-G is Pathogenic according to our data. Variant chr1-153816570-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 419376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATAD2B	NM_020699.4	c.918del	p.Pro307HisfsTer12	frameshift_variant	7/11	ENST00000368655.5
GATAD2B	XM_047426115.1	c.921del	p.Pro308HisfsTer12	frameshift_variant	7/11
GATAD2B	XM_047426117.1	c.918del	p.Pro307HisfsTer12	frameshift_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATAD2B	ENST00000368655.5	c.918del	p.Pro307HisfsTer12	frameshift_variant	7/11	1	NM_020699.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Feb 26, 2017	This 7 year old male with mild-moderate intellectual disability, childhood apraxia of speech, macrocephaly (>98th percentile), mild neuromotor abnormalities, and anisocoria was found to carry a de novo 1 bp deletion in the GATAD2B gene. Pathogenic variants in this gene are associated with intellectual disability, limited language development, esotropia, and dysmorphic features. This patient has been noted to have macrocephaly with mild scaphocephaly, a broad forehead, an extra hair whorl, palpebral fissures with slight downward slant, and slightly anteverted nares. This variant is absent from population databases, and it is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2019

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31949314) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1064793829; hg19: chr1-153789046;