chr1-153810241-C-T

Position:

• chr1-153810241-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_020699.4(GATAD2B):​c.1718G>A​(p.Arg573His) 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATAD2B NM_020699.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.88

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GATAD2B. . Gene score misZ 3.161 (greater than the threshold 3.09). Trascript score misZ 3.9812 (greater than threshold 3.09). GenCC has associacion of gene with severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATAD2B	NM_020699.4	c.1718G>A	p.Arg573His	missense_variant	11/11	ENST00000368655.5	NP_065750.1
GATAD2B	XM_047426115.1	c.1721G>A	p.Arg574His	missense_variant	11/11		XP_047282071.1
GATAD2B	XM_047426117.1	c.1718G>A	p.Arg573His	missense_variant	11/11		XP_047282073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATAD2B	ENST00000368655.5	c.1718G>A	p.Arg573His	missense_variant	11/11	1	NM_020699.4	ENSP00000357644	P1
GATAD2B	ENST00000634544.1	c.1718G>A	p.Arg573His	missense_variant	11/11	5		ENSP00000489184	P1
GATAD2B	ENST00000634408.1	c.1670G>A	p.Arg557His	missense_variant	11/11	5		ENSP00000489595
GATAD2B	ENST00000637918.1	c.135+1490G>A		intron_variant		5		ENSP00000490724

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 12, 2024

Variant summary: GATAD2B c.1718G>A (p.Arg573His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248460 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1718G>A in individuals affected with Severe Intellectual Disability-Poor Language-Strabismus Face-Long Fingers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2024

The c.1718G>A (p.R573H) alteration is located in exon 11 (coding exon 10) of the GATAD2B gene. This alteration results from a G to A substitution at nucleotide position 1718, causing the arginine (R) at amino acid position 573 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D;.;.
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.55		Gain of catalytic residue at R571 (P = 0.0608);Gain of catalytic residue at R571 (P = 0.0608);.;
MVP		0.81
MPC		2.1
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.65
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-153782717; COSMIC: COSV64084605; COSMIC: COSV64084605;