rs372276373

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_020699.4(GATAD2B):c.1753A>G(p.Ile585Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,612,452 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

GATAD2B
NM_020699.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 7.99

Publications

1 publications found

Variant links:

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)

GATAD2B links:

ENSG00000291199 (HGNC:):

ENSG00000291199 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 1-153810206-T-C is Benign according to our data. Variant chr1-153810206-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211067.

BS2

High AC in GnomAdExome4 at 118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GATAD2B	NM_020699.4 link	c.1753A>G	p.Ile585Val	missense_variant	Exon 11 of 11	ENST00000368655.5	NP_065750.1
GATAD2B	XM_047426115.1 link	c.1756A>G	p.Ile586Val	missense_variant	Exon 11 of 11		XP_047282071.1
GATAD2B	XM_047426117.1 link	c.1753A>G	p.Ile585Val	missense_variant	Exon 11 of 11		XP_047282073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATAD2B	ENST00000368655.5 link	c.1753A>G	p.Ile585Val	missense_variant	Exon 11 of 11	1	NM_020699.4	ENSP00000357644.4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000321

AC:

AN:

249232

AF XY:

0.0000445

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000710

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000808

AC:

118

AN:

1460246

Hom.:

Cov.:

AF XY:

0.0000812

AC XY:

AN XY:

726432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33366

American (AMR)

AF:

0.00

AC:

AN:

44328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.00

AC:

AN:

85982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000101

AC:

112

AN:

1111372

Other (OTH)

AF:

0.0000995

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 585 of the GATAD2B protein (p.Ile585Val). This variant is present in population databases (rs372276373, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with GATAD2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 211067). 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 not expected to disrupt GATAD2B protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GATAD2B: BS2 -

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

Uncertain:1

Jun 13, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Benign:1

Dec 02, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 06, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Benign

0.0073

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

M;M;.

PhyloP100

8.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.50

N;.;.

REVEL

Benign

0.19

Sift

Uncertain

0.011

D;.;.

Sift4G

Uncertain

0.030

D;D;D

Polyphen

0.80

P;P;.

Vest4

0.46

MVP

0.26

MPC

1.7

ClinPred

0.28

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.67

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.25

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over