1-153810197-A-C

Position:

• chr1-153810197-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_020699.4(GATAD2B):​c.1762T>G​(p.Ser588Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S588C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATAD2B NM_020699.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.35

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 1 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=0.19099078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATAD2B	NM_020699.4	c.1762T>G	p.Ser588Ala	missense_variant	11/11	ENST00000368655.5
GATAD2B	XM_047426115.1	c.1765T>G	p.Ser589Ala	missense_variant	11/11
GATAD2B	XM_047426117.1	c.1762T>G	p.Ser588Ala	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATAD2B	ENST00000368655.5	c.1762T>G	p.Ser588Ala	missense_variant	11/11	1	NM_020699.4	P1
GATAD2B	ENST00000634544.1	c.1762T>G	p.Ser588Ala	missense_variant	11/11	5		P1
GATAD2B	ENST00000634408.1	c.1714T>G	p.Ser572Ala	missense_variant	11/11	5
GATAD2B	ENST00000637918.1	c.135+1534T>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense c.1762T>G(p.Ser588Ala) variant in GATAD2B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in gnomAD Exomes. The amino acid Ser at position 588 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser588Ala in GATAD2B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Polyphen - Benign, SIFT - Tolerated, and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T;T;.
Eigen	Benign	0.098
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.60	.;.;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.0	N;.;.
REVEL	Benign	0.093
Sift	Benign	0.058	T;.;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.12	B;B;.
Vest4		0.35
MutPred		0.16		Loss of phosphorylation at S588 (P = 0.0243);Loss of phosphorylation at S588 (P = 0.0243);.;
MVP		0.25
MPC		1.3
ClinPred		0.72	D
GERP RS		5.4
Varity_R		0.11
gMVP		0.78

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: chr1-153782673;