chr7-92447786-G-A

Variant names:

• chr7-92447786-G-A
• rs1789217100
• NM_021167.5:c.57G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021167.5(GATAD1):​c.57G>A​(p.Met19Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000743 in 1,345,632 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: GATAD1 NM_021167.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16
• Publications: 0 publications found

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]

GATAD1 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 2B

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

TMBIM7P (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATAD1	NM_021167.5	c.57G>A	p.Met19Ile	missense_variant	Exon 1 of 5	ENST00000287957.5	NP_066990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATAD1	ENST00000287957.5	c.57G>A	p.Met19Ile	missense_variant	Exon 1 of 5	1	NM_021167.5	ENSP00000287957.3
TMBIM7P	ENST00000641474.1	n.28C>T		non_coding_transcript_exon_variant	Exon 1 of 10
GATAD1	ENST00000645746.1	n.57G>A		non_coding_transcript_exon_variant	Exon 1 of 6			ENSP00000493785.1
GATAD1	ENST00000644160.1	n.-88G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345632 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 663688

African (AFR) AF: 0.00 AC: 0 AN: 26890

American (AMR) AF: 0.00 AC: 0 AN: 28608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23506

East Asian (EAS) AF: 0.00 AC: 0 AN: 28388

South Asian (SAS) AF: 0.00 AC: 0 AN: 74926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5556

European-Non Finnish (NFE) AF: 9.48e-7 AC: 1 AN: 1055128

Other (OTH) AF: 0.00 AC: 0 AN: 55374

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 2B Uncertain:1

Dec 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with isoleucine at codon 19 of the GATAD1 protein (p.Met19Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with GATAD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	L
PhyloP100		5.2
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.66
Sift	Benign	0.11	T
Sift4G	Benign	0.27	T
Polyphen		0.39	B
Vest4		0.48
MutPred		0.43		Loss of helix (P = 0.079);
MVP		0.61
MPC		0.46
ClinPred		0.93	D
GERP RS		4.5
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.45
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs1789217100; hg19: chr7-92077100;