rs387906816

chr18-22171695-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:3 B:3
• Conservation: PhyloP100: 3.16

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]

ACMG classification

Verdict is Benign. Variant got -16 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 [Likely_benign]. Clinvar id is 30210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA6	NM_005257.6	c.551G>A	p.Ser184Asn	missense_variant	2/7	ENST00000269216.10
GATA6	XM_047437483.1	c.551G>A	p.Ser184Asn	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA6	ENST00000269216.10	c.551G>A	p.Ser184Asn	missense_variant	2/7	1	NM_005257.6	P1
GATA6	ENST00000581694.1	c.551G>A	p.Ser184Asn	missense_variant	1/6	1		P1

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

GnomAD3 exomes AF: 0.000836 AC: 82 AN: 98138 Hom.: 1 AF XY: 0.000898 AC XY: 50 AN XY: 55680

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 SAS exome AF: 0.000690

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00688

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000394

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00549

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000463 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.000571 AC: 13

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:3 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrial septal defect 9 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2010	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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; -

Atrioventricular septal defect 5 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Tetralogy of Fallot Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2021

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	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0091	T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.85	L;L
MutationTaster	Benign	0.96	N;N
PrimateAI	Pathogenic	0.93	D
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	T
GERP RS		1.8
Varity_R		0.071
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs387906816; hg19: chr18-19751656;