7-92447886-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021167.5(GATAD1):c.157G>C(p.Gly53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,278,914 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G53W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: GATAD1 NM_021167.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.65

Genes affected

GATAD1 (HGNC:29941): (GATA zinc finger domain containing 1) The protein encoded by this gene contains a zinc finger at the N-terminus, and is thought to bind to a histone modification site that regulates gene expression. Mutations in this gene have been associated with autosomal recessive dilated cardiomyopathy. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19825971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATAD1	NM_021167.5	c.157G>C	p.Gly53Arg	missense_variant	1/5	ENST00000287957.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATAD1	ENST00000287957.5	c.157G>C	p.Gly53Arg	missense_variant	1/5	1	NM_021167.5	P1
GATAD1	ENST00000644160.1	n.13G>C		non_coding_transcript_exon_variant	1/2
GATAD1	ENST00000645746.1	c.157G>C	p.Gly53Arg	missense_variant, NMD_transcript_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151936 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00321

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000231 AC: 26 AN: 1126978 Hom.: 0 Cov.: 30 AF XY: 0.0000204 AC XY: 11 AN XY: 539858

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: 0.0000265

Gnomad4 OTH exome AF: 0.0000222

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151936 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74234

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 2B Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 18, 2022	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. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 53 of the GATAD1 protein (p.Gly53Arg). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GATAD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 23, 2021	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2019

The p.G53R variant (also known as c.157G>C), located in coding exon 1 of the GATAD1 gene, results from a G to C substitution at nucleotide position 157. The glycine at codon 53 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.21	N
REVEL	Uncertain	0.30
Sift	Benign	0.073	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.73	P
Vest4		0.17
MutPred		0.32		Gain of methylation at G53 (P = 0.0052);
MVP		0.39
MPC		0.36
ClinPred		0.41	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.16

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: rs988478105; hg19: chr7-92077200;