chr18-22171695-G-A

Variant names:

• chr18-22171695-G-A
• rs387906816
• NM_005257.6:c.551G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 4P and 13B. PS3 BP4_Strong BP6 BS1 BS2

The NM_005257.6(GATA6):​c.551G>A​(p.Ser184Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,498,160 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001142479: Functional studies demonstrate that this variant clearly decreased transcriptional activity of GATA6 Ser184Asn in vitro (PMID:20631719).".

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 B:3
• Conservation: PhyloP100: 3.16
• Publications: 20 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: Ambry Genetics, G2P
• atrioventricular septal defect 5

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, Genomics England PanelApp
• 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
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001142479: Functional studies demonstrate that this variant clearly decreased transcriptional activity of GATA6 Ser184Asn in vitro (PMID: 20631719).
• BP4: Computational evidence support a benign effect (MetaRNN=0.009056032).
• BP6: Variant 18-22171695-G-A is Benign according to our data. Variant chr18-22171695-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30210.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000217 (33/151800) while in subpopulation EAS AF = 0.00549 (28/5102). AF 95% confidence interval is 0.0039. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD 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.551G>A	p.Ser184Asn	missense	Exon 2 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.551G>A	p.Ser184Asn	missense	Exon 2 of 7	ENSP00000269216.3	Q92908-1
	GATA6	ENST00000581694.1	TSL:1	c.551G>A	p.Ser184Asn	missense	Exon 1 of 6	ENSP00000462313.1	Q92908-1
	GATA6	ENST00000853536.1		c.551G>A	p.Ser184Asn	missense	Exon 2 of 8	ENSP00000523595.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151692 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00567

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000836 AC: 82 AN: 98138 AF XY: 0.000898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0102

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000253 AC: 341 AN: 1346360 Hom.: 3 Cov.: 30 AF XY: 0.000293 AC XY: 195 AN XY: 664938

African (AFR) AF: 0.00 AC: 0 AN: 26992

American (AMR) AF: 0.00 AC: 0 AN: 29054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23702

East Asian (EAS) AF: 0.00688 AC: 222 AN: 32270

South Asian (SAS) AF: 0.000649 AC: 49 AN: 75470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34078

Middle Eastern (MID) AF: 0.000228 AC: 1 AN: 4384

European-Non Finnish (NFE) AF: 0.0000441 AC: 47 AN: 1064558

Other (OTH) AF: 0.000394 AC: 22 AN: 55852

GnomAD4 genome AF: 0.000217 AC: 33 AN: 151800 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74180

African (AFR) AF: 0.00 AC: 0 AN: 41514

American (AMR) AF: 0.0000656 AC: 1 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00549 AC: 28 AN: 5102

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10462

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

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67868

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000463 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.000571 AC: 13

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Atrial septal defect 9 (2)
-	-	2	Atrioventricular septal defect 5 (2)
-	-	1	not provided (1)
1	-	-	Tetralogy of Fallot (1)
-	1	-	Tetralogy of Fallot;C1857586:Conotruncal heart malformations;C2931296:Pancreatic hypoplasia-diabetes-congenital heart disease syndrome;C3280939:Atrioventricular septal defect 5;C3280943:Atrial septal defect 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.85	L
PhyloP100		3.2
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.32
Sift	Benign	0.067	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.57
MutPred		0.57		Loss of glycosylation at S184 (P = 1e-04)
MVP		0.85
ClinPred		0.036	T
GERP RS		1.8
Varity_R		0.071
gMVP		0.27
Mutation Taster		=93/7	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: rs387906816; hg19: chr18-19751656;