7-92447913-G-A

Position:

• chr7-92447913-G-A

Variant summary

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

The NM_021167.5(GATAD1):​c.184G>A​(p.Ala62Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000818 in 1,100,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GATAD1 NM_021167.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.213

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=0.12538251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATAD1	NM_021167.5	c.184G>A	p.Ala62Thr	missense_variant	1/5	ENST00000287957.5	NP_066990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATAD1	ENST00000287957.5	c.184G>A	p.Ala62Thr	missense_variant	1/5	1	NM_021167.5	ENSP00000287957	P1
GATAD1	ENST00000644160.1	n.40G>A		non_coding_transcript_exon_variant	1/2
GATAD1	ENST00000645746.1	c.184G>A	p.Ala62Thr	missense_variant, NMD_transcript_variant	1/6			ENSP00000493785

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000818 AC: 9 AN: 1100646 Hom.: 0 Cov.: 32 AF XY: 0.00000952 AC XY: 5 AN XY: 525248

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: 0.00000965

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 2B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 62 of the GATAD1 protein (p.Ala62Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GATAD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1012067). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The p.A62T variant (also known as c.184G>A), located in coding exon 1 of the GATAD1 gene, results from a G to A substitution at nucleotide position 184. The alanine at codon 62 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	0.066
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.16
Sift	Benign	0.54	T
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.065
MutPred		0.17		Gain of phosphorylation at A62 (P = 0.031);
MVP		0.34
MPC		0.29
ClinPred		0.050	T
GERP RS		-0.080
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.038
gMVP		0.12

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: rs1445688677; hg19: chr7-92077227;