7-92454670-G-C

Variant names:

• chr7-92454670-G-C
• rs564747350
• NM_021167.5:c.604G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021167.5(GATAD1):​c.604G>C​(p.Ala202Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,439,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A202T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GATAD1 NM_021167.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021167.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATAD1	NM_021167.5	MANE Select	c.604G>C	p.Ala202Pro	missense	Exon 4 of 5	NP_066990.3
	GATAD1	NR_052016.2		n.852G>C		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATAD1	ENST00000287957.5	TSL:1 MANE Select	c.604G>C	p.Ala202Pro	missense	Exon 4 of 5	ENSP00000287957.3	Q8WUU5
	GATAD1	ENST00000493878.1	TSL:1	n.1212G>C		non_coding_transcript_exon	Exon 2 of 3
	GATAD1	ENST00000465247.1	TSL:2	n.616G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1439724 Hom.: 0 Cov.: 29 AF XY: 0.00000280 AC XY: 2 AN XY: 715260

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32334

American (AMR) AF: 0.00 AC: 0 AN: 39500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25390

East Asian (EAS) AF: 0.00 AC: 0 AN: 39186

South Asian (SAS) AF: 0.00 AC: 0 AN: 81244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1103500

Other (OTH) AF: 0.00 AC: 0 AN: 59568

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0136242), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.5	L
PhyloP100		4.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.53
Sift	Benign	0.066	T
Sift4G	Uncertain	0.033	D
Polyphen		0.98	D
Vest4		0.74
MutPred		0.24		Gain of catalytic residue at P201 (P = 0.0127)
MVP		0.61
MPC		0.81
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.62
gMVP		0.61
Mutation Taster		=54/46	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: rs564747350; hg19: chr7-92083984;