rs34768413

chr7-92456449-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021167.5(GATAD1):c.697C>T(p.Arg233Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,611,378 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R233Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.015 (218 hom.)
• Consequence: GATAD1 NM_021167.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.27

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008320868).
• BP6: Variant 7-92456449-C-T is Benign according to our data. Variant chr7-92456449-C-T is described in ClinVar as [Benign]. Clinvar id is 45829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92456449-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0152 (22210/1459056) while in subpopulation MID AF= 0.0193 (111/5766). AF 95% confidence interval is 0.0176. There are 218 homozygotes in gnomad4_exome. There are 11048 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATAD1	NM_021167.5	c.697C>T	p.Arg233Trp	missense_variant	5/5	ENST00000287957.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATAD1	ENST00000287957.5	c.697C>T	p.Arg233Trp	missense_variant	5/5	1	NM_021167.5	P1
GATAD1	ENST00000493878.1	n.1305C>T		non_coding_transcript_exon_variant	3/3	1
GATAD1	ENST00000465247.1	n.709C>T		non_coding_transcript_exon_variant	2/2	2
GATAD1	ENST00000645746.1	c.*288C>T		3_prime_UTR_variant, NMD_transcript_variant	6/6

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1525 AN: 152204 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0109 AC: 2734 AN: 251366 Hom.: 16 AF XY: 0.0114 AC XY: 1542 AN XY: 135854

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0152 AC: 22210 AN: 1459056 Hom.: 218 Cov.: 29 AF XY: 0.0152 AC XY: 11048 AN XY: 725958

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.00725

Gnomad4 ASJ exome AF: 0.00525

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00339

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0100 AC: 1525 AN: 152322 Hom.: 16 Cov.: 32 AF XY: 0.00975 AC XY: 726 AN XY: 74484

Gnomad4 AFR AF: 0.00240

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0155 Hom.: 47

Bravo AF: 0.00982

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0111 AC: 1353

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Arg233Trp in Exon 05 of GATAD1: This variant is not expected to have clinical significance because it has been identified in 1.5% (107/7020) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs34768413). -

Dilated cardiomyopathy 2B Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.061
MPC		0.79
ClinPred		0.057	T
GERP RS		3.5
Varity_R		0.47
gMVP		0.68

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: rs34768413; hg19: chr7-92085763; COSMIC: COSV99072876; COSMIC: COSV99072876;