8-11708855-C-T

Variant names:

• chr8-11708855-C-T
• rs544097659
• NM_001308093.3:c.543C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001308093.3(GATA4):​c.543C>T​(p.Ala181Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,503,872 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A181A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (4 hom.)
• Consequence: GATA4 NM_001308093.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.341
• Publications: 1 publications found

Genes affected

GATA4 (HGNC:4173): (GATA binding protein 4) This gene encodes a member of the GATA family of zinc-finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function, and is necessary for normal testicular development. Mutations in this gene have been associated with cardiac septal defects. Additionally, alterations in gene expression have been associated with several cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

GATA4 Gene-Disease associations (from GenCC):

• atrial septal defect 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• structural congenital heart disease, multiple types - GATA4

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• testicular anomalies with or without congenital heart disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• metabolic syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• pancreatic hypoplasia-diabetes-congenital heart disease syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tetralogy of fallot

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 8-11708855-C-T is Benign according to our data. Variant chr8-11708855-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 412729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.341 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00211 (321/152096) while in subpopulation AFR AF = 0.00715 (297/41530). AF 95% confidence interval is 0.00648. There are 1 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 321 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308093.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA4	NM_001308093.3	MANE Select	c.543C>T	p.Ala181Ala	synonymous	Exon 2 of 7	NP_001295022.1
	GATA4	NM_002052.5		c.543C>T	p.Ala181Ala	synonymous	Exon 2 of 7	NP_002043.2
	GATA4	NM_001308094.2		c.-6+8077C>T		intron	N/A	NP_001295023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA4	ENST00000532059.6	TSL:1 MANE Select	c.543C>T	p.Ala181Ala	synonymous	Exon 2 of 7	ENSP00000435712.1
	GATA4	ENST00000335135.8	TSL:5	c.543C>T	p.Ala181Ala	synonymous	Exon 2 of 7	ENSP00000334458.4
	GATA4	ENST00000622443.3	TSL:5	c.543C>T	p.Ala181Ala	synonymous	Exon 3 of 8	ENSP00000482268.2

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 320 AN: 151990 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00715

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000169 AC: 17 AN: 100558 AF XY: 0.000177

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.000192

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000206 AC: 278 AN: 1351776 Hom.: 4 Cov.: 31 AF XY: 0.000183 AC XY: 122 AN XY: 666882

African (AFR) AF: 0.00849 AC: 233 AN: 27434

American (AMR) AF: 0.000339 AC: 11 AN: 32406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23956

East Asian (EAS) AF: 0.00 AC: 0 AN: 31920

South Asian (SAS) AF: 0.0000262 AC: 2 AN: 76274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33260

Middle Eastern (MID) AF: 0.000249 AC: 1 AN: 4022

European-Non Finnish (NFE) AF: 0.00000469 AC: 5 AN: 1066248

Other (OTH) AF: 0.000462 AC: 26 AN: 56256

GnomAD4 genome AF: 0.00211 AC: 321 AN: 152096 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74366

African (AFR) AF: 0.00715 AC: 297 AN: 41530

American (AMR) AF: 0.000916 AC: 14 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67950

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.0000941 Hom.: 0

Bravo AF: 0.00241

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Atrioventricular septal defect 4 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.4
DANN	Benign	0.95
PhyloP100		-0.34

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: rs544097659; hg19: chr8-11566364;