rs587776931

Variant names:

• chr1-153813261-G-A
• rs587776931
• NM_020699.4:c.1408C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020699.4(GATAD2B):​c.1408C>T​(p.Gln470*) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATAD2B NM_020699.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.97
• Publications: 3 publications found

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]

GATAD2B Gene-Disease associations (from GenCC):

• severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Illumina, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000291199 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 1-153813261-G-A is Pathogenic according to our data. Variant chr1-153813261-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATAD2B	NM_020699.4	c.1408C>T	p.Gln470*	stop_gained	Exon 8 of 11	ENST00000368655.5	NP_065750.1
GATAD2B	XM_047426115.1	c.1411C>T	p.Gln471*	stop_gained	Exon 8 of 11		XP_047282071.1
GATAD2B	XM_047426117.1	c.1408C>T	p.Gln470*	stop_gained	Exon 8 of 11		XP_047282073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATAD2B	ENST00000368655.5	c.1408C>T	p.Gln470*	stop_gained	Exon 8 of 11	1	NM_020699.4	ENSP00000357644.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jan 03, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1408C>T (p.Q470*) alteration, located in exon 8 (coding exon 7) of the GATAD2B gene, results from a C to T substitution at nucleotide position 1408. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 470. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GATAD2B c.1408C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was previously detected de novo in two unrelated patients with intellectual disability (de Ligt, 2012; Kosmicki, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Jul 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28191890, 35982159, 23644463, 23033978, 34470925, 30482549, 24896178) -

Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome Pathogenic:1

Nov 15, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		10
Vest4		0.47
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587776931; hg19: chr1-153785737;