rs387906816

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 3 hom. )

Consequence

GATA6
NM_005257.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1B:3

Conservation

PhyloP100: 3.16

Publications

20 publications found

Variant links:

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

GATA6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

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 id is 30210.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

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 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA6	NM_005257.6 link	c.551G>A	p.Ser184Asn	missense_variant	Exon 2 of 7	ENST00000269216.10	NP_005248.2	Q92908-1
GATA6	XM_047437483.1 link	c.551G>A	p.Ser184Asn	missense_variant	Exon 2 of 7		XP_047293439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA6	ENST00000269216.10 link	c.551G>A	p.Ser184Asn	missense_variant	Exon 2 of 7	1	NM_005257.6	ENSP00000269216.3		Q92908-1
GATA6	ENST00000581694.1 link	c.551G>A	p.Ser184Asn	missense_variant	Exon 1 of 6	1		ENSP00000462313.1		Q92908-1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

151692

Hom.:

Cov.:

show subpopulations

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:

AN:

98138

AF XY:

0.000898

show subpopulations

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.:

Cov.:

AF XY:

0.000293

AC XY:

195

AN XY:

664938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26992

American (AMR)

AF:

0.00

AC:

AN:

29054

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23702

East Asian (EAS)

AF:

0.00688

AC:

222

AN:

32270

South Asian (SAS)

AF:

0.000649

AC:

AN:

75470

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34078

Middle Eastern (MID)

AF:

0.000228

AC:

AN:

4384

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

1064558

Other (OTH)

AF:

0.000394

AC:

AN:

55852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000217

AC:

AN:

151800

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41514

American (AMR)

AF:

0.0000656

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00549

AC:

AN:

5102

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67868

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000463

Hom.:

Bravo

AF:

0.000242

ExAC

AF:

0.000571

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Atrial septal defect 9

Pathogenic:2

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

NM_005257.4:c.551G>A in the GATA6 gene has an allele frequency of 0.009 in East Asia subpopulation in the gnomAD database. Functional studies demonstrate that this variant clearly decreased transcriptional activity of GATA6 Ser184Asn in vitro (PMID: 20631719). In addition, Wang et al. identified c.551G>A in a patient with Tetralogy of Fallot. His parents had normal cardiac morphology and there were no GATA6 sequence variants identified, indicating a de novo event (PMID: 24841381). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM2; PM6; -

Oct 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Atrioventricular septal defect 5

Benign:2

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tetralogy of Fallot

Pathogenic:1

Oct 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Uncertain:1

Mar 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 25, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20631719, 24841381, 29101065, 31949757, 22498567, 34426522) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.82

D;D

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.69

.;T

MetaRNN

Benign

0.0091

T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

0.85

L;L

PhyloP100

3.2

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.92

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.067

T;.

Sift4G

Benign

0.20

T;T

Polyphen

0.0010

B;B

Vest4

0.57

MutPred

0.57

Loss of glycosylation at S184 (P = 1e-04);Loss of glycosylation at S184 (P = 1e-04);

MVP

0.85

ClinPred

0.036

GERP RS

1.8

Varity_R

0.071

gMVP

0.27

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over