rs115099192

chr8-11758366-C-Achr8-11758366-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001308093.3(GATA4):c.1223C>A(p.Pro408Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000381 in 1,614,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P408A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:3
• Conservation: PhyloP100: 4.87

Genes affected

GATA4 (HGNC:4173): (GATA binding protein 4) This gene encodes a member of the GATA family of zinc-finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function, and is necessary for normal testicular development. Mutations in this gene have been associated with cardiac septal defects. Additionally, alterations in gene expression have been associated with several cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011231691).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000276 (42/152348) while in subpopulation EAS AF= 0.00367 (19/5182). AF 95% confidence interval is 0.0024. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3	c.1223C>A	p.Pro408Gln	missense_variant	7/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6	c.1223C>A	p.Pro408Gln	missense_variant	7/7	1	NM_001308093.3	A1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000513 AC: 129 AN: 251464 Hom.: 0 AF XY: 0.000493 AC XY: 67 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00353

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000392 AC: 573 AN: 1461874 Hom.: 1 Cov.: 31 AF XY: 0.000403 AC XY: 293 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00806

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000674

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74500

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tetralogy of Fallot Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2008

- -

Ventricular septal defect 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2010

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 31, 2019

Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 TOF patient (sporadic) (Zhang 2008), in 3 individuals (het) with disorders of sexual develpment (Eggers 2016). Liu 2017 further reported this variant in 4/600 patients with conotruncal heart defects and 1/300 controls. Qian 2017 reported the variant in 2 individuals with TOF and POF (also carried V380M, previously associated with VSD))). Identified in 0.3% of East Asian chromosomes in gnomAD. Present in ClinVar (ID 30103) with conflicting interpretations (B, Uncertain significance). -

Microcephaly Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

-

- -

Atrial septal defect 2;C3280777:Ventricular septal defect 1;C3280781:Atrioventricular septal defect 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2023

Identified in several individuals with congenital heart defects (Zhang et al., 2008; Hamanoue et al., 2009; Peng et al., 2010; Wang et al., 2010; Dinesh et al., 2011; Yoshida et al., 2016; Liu et al., 2017; Qian et al., 2017; Dixit et al., 2018; Kalayinia et al., 2019) and in healthy control individuals in published literature (Hamanoue et al., 2009; Yoshida et al., 2016; Liu et al., 2017; Qian et al., 2017); Also identified in association with early onset diabetes (Kwak et al., 2016) and disorders of sexual development, including individuals without heart anomalies (Eggers et al 2016; Igarashi et al., 2018); Functional studies show inconsistent data, including one study that found p.(P407Q) results in ~50% reduction in transactivation compared to wild type protein (Igarashi et al., 2018), whereas another study showed protein behavior similar to wild type (van den Bergen et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19678963, 26490186, 24583203, 18672102, 21110066, 20654103, 20592452, 22648249, 22959235, 26997702, 27810688, 27899157, 28161810, 28372585, 29735817, 30152191, 31115957, 21631294, 31513339, 31962012, 34426522, 32508047) -

Testicular anomalies with or without congenital heart disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with GATA4-related cardiac disease. (I) 0107 - This gene is associated with autosomal dominant disease. A number a different cardiac conditions are caused by variants in GATA4 , however association with differences of sex development (DSD) is not well-established (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to glutamine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of GATA4-related cardiac disease (gnomAD (v2) 132 heterozygotes, 0 homozygotes). (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (17 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated zinc finger DNA binding domain (NCBI). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Alternative changes at the same residue, to alanine and arginine, have previously been classified as VUS in relation to atrioventricular septal defect (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting for both cardiac and DSD conditions, however more recent reports consistently report the variant as benign in relation to DSD (ClinVar, LOVD, HGMD, OMIM, PMID: 32992319). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Atrioventricular septal defect 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

46,XY sex reversal 3 Benign:1

Benign, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Aug 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0056	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.35	T;D;.;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N;D;D;.
REVEL	Pathogenic	0.71
Sift	Benign	0.032	D;D;D;.
Sift4G	Benign	0.092	T;T;T;T
Polyphen		0.68	.;P;.;.
Vest4		0.38
MVP		0.94
MPC		0.18
ClinPred		0.090	T
GERP RS		4.8
Varity_R		0.26
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs115099192; hg19: chr8-11615875;