rs117646477

Variant names:

• chr18-22183028-A-G
• rs117646477
• NM_005257.6:c.1605A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_005257.6(GATA6):​c.1605A>G​(p.Gln535Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 1,612,286 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (11 hom.)
• Consequence: GATA6 NM_005257.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.782
• Publications: 2 publications found

Genes affected

GATA6 (HGNC:4174): (GATA binding protein 6) This gene is a member of a small family of zinc finger transcription factors that play an important role in the regulation of cellular differentiation and organogenesis during vertebrate development. This gene is expressed during early embryogenesis and localizes to endo- and mesodermally derived cells during later embryogenesis and thereby plays an important role in gut, lung, and heart development. Mutations in this gene are associated with several congenital defects. [provided by RefSeq, Mar 2012]

GATA6 Gene-Disease associations (from GenCC):

• atrial septal defect 9

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics
• atrioventricular septal defect 5

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pancreatic hypoplasia-diabetes-congenital heart disease syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• metabolic syndrome

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tetralogy of fallot

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• conotruncal heart malformations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 18-22183028-A-G is Benign according to our data. Variant chr18-22183028-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240129.
• BP7: Synonymous conserved (PhyloP=0.782 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000644 (98/152230) while in subpopulation SAS AF = 0.00622 (30/4822). AF 95% confidence interval is 0.00448. There are 1 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005257.6. 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
	GATA6	NM_005257.6	MANE Select	c.1605A>G	p.Gln535Gln	synonymous	Exon 6 of 7	NP_005248.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA6	ENST00000269216.10	TSL:1 MANE Select	c.1605A>G	p.Gln535Gln	synonymous	Exon 6 of 7	ENSP00000269216.3
	GATA6	ENST00000581694.1	TSL:1	c.1605A>G	p.Gln535Gln	synonymous	Exon 5 of 6	ENSP00000462313.1
	GATA6	ENST00000853536.1		c.1713A>G	p.Gln571Gln	synonymous	Exon 7 of 8	ENSP00000523595.1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.0113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00154 AC: 387 AN: 251400 AF XY: 0.00185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000955 AC: 1394 AN: 1460056 Hom.: 11 Cov.: 31 AF XY: 0.00119 AC XY: 861 AN XY: 726472

African (AFR) AF: 0.000120 AC: 4 AN: 33446

American (AMR) AF: 0.000447 AC: 20 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 335 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00619 AC: 534 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.000342 AC: 380 AN: 1110344

Other (OTH) AF: 0.00143 AC: 86 AN: 60328

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74428

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.000196 AC: 3 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 39 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.000638

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Atrioventricular septal defect 5 (1)
-	1	-	Neonatal insulin-dependent diabetes mellitus (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.8
DANN	Benign	0.79
PhyloP100		0.78
Mutation Taster		=100/0	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: rs117646477; hg19: chr18-19762989;