7-92447791-A-G

Variant summary

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

The NM_021167.5(GATAD1):c.62A>G(p.Lys21Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000521 in 1,344,524 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: GATAD1 NM_021167.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.71

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]

TMBIM7P (HGNC:49212): (transmembrane BAX inhibitor motif containing 7, pseudogene)

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=0.17456245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATAD1	NM_021167.5	c.62A>G	p.Lys21Arg	missense_variant	1/5	ENST00000287957.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATAD1	ENST00000287957.5	c.62A>G	p.Lys21Arg	missense_variant	1/5	1	NM_021167.5	P1
TMBIM7P	ENST00000641474.1	n.23T>C		non_coding_transcript_exon_variant	1/10
GATAD1	ENST00000645746.1	c.62A>G	p.Lys21Arg	missense_variant, NMD_transcript_variant	1/6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000521 AC: 7 AN: 1344524 Hom.: 0 Cov.: 31 AF XY: 0.00000452 AC XY: 3 AN XY: 663148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000352

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: 0.00000569

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Invitae

Nov 11, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 21 of the GATAD1 protein (p.Lys21Arg). 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: 1752705). 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 GATAD1 protein function with a negative predictive value of 80%. 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

Jan 20, 2021

The p.K21R variant (also known as c.62A>G), located in coding exon 1 of the GATAD1 gene, results from an A to G substitution at nucleotide position 62. The lysine at codon 21 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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	0.082
BayesDel_addAF	Benign	0.0090	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Benign	0.64
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	-0.36	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.75	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	0.85	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.26		Loss of methylation at K21 (P = 0.0111);
MVP		0.30
MPC		0.25
ClinPred		0.067	T
GERP RS		3.3
Varity_R		0.049
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1562816127; hg19: chr7-92077105;