chr1-153810202-G-A

Position:

• chr1-153810202-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_020699.4(GATAD2B):​c.1757C>T​(p.Ser586Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. S586S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GATAD2B NM_020699.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3295561).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATAD2B	NM_020699.4	c.1757C>T	p.Ser586Leu	missense_variant	11/11	ENST00000368655.5
GATAD2B	XM_047426115.1	c.1760C>T	p.Ser587Leu	missense_variant	11/11
GATAD2B	XM_047426117.1	c.1757C>T	p.Ser586Leu	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATAD2B	ENST00000368655.5	c.1757C>T	p.Ser586Leu	missense_variant	11/11	1	NM_020699.4	P1
GATAD2B	ENST00000634544.1	c.1757C>T	p.Ser586Leu	missense_variant	11/11	5		P1
GATAD2B	ENST00000634408.1	c.1709C>T	p.Ser570Leu	missense_variant	11/11	5
GATAD2B	ENST00000637918.1	c.135+1529C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459964 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GATAD2B protein function. This variant has not been reported in the literature in individuals affected with GATAD2B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 586 of the GATAD2B protein (p.Ser586Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D;.;.
REVEL	Benign	0.29
Sift	Benign	0.057	T;.;.
Sift4G	Uncertain	0.032	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.36
MutPred		0.31		Gain of catalytic residue at S586 (P = 0.0081);Gain of catalytic residue at S586 (P = 0.0081);.;
MVP		0.22
MPC		0.76
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.32
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-153782678; COSMIC: COSV64083666; COSMIC: COSV64083666;