rs587776931

Positions:

• chr1-153813261-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020699.4(GATAD2B):​c.1408C>T​(p.Gln470Ter) 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, single submitter P:2
• Conservation: PhyloP100: 9.97

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 12 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 id is 39665.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-153813261-G-A is described in Lovd as [Pathogenic]. Variant chr1-153813261-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATAD2B	NM_020699.4	c.1408C>T	p.Gln470Ter	stop_gained	8/11	ENST00000368655.5
GATAD2B	XM_047426115.1	c.1411C>T	p.Gln471Ter	stop_gained	8/11
GATAD2B	XM_047426117.1	c.1408C>T	p.Gln470Ter	stop_gained	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATAD2B	ENST00000368655.5	c.1408C>T	p.Gln470Ter	stop_gained	8/11	1	NM_020699.4	P1
GATAD2B	ENST00000634544.1	c.1408C>T	p.Gln470Ter	stop_gained	8/11	5		P1
GATAD2B	ENST00000634408.1	c.1360C>T	p.Gln454Ter	stop_gained	8/11	5
GATAD2B	ENST00000634564.1	c.664C>T	p.Gln222Ter	stop_gained	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2020

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. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 2012

- -

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
MutationTaster	Benign	1.0	A
Vest4		0.47
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776931; hg19: chr1-153785737;