rs904519303

chr18-22171983-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005257.6(GATA6):c.839G>C(p.Gly280Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000576 in 1,221,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.29

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3676116).
• BS2: High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA6	NM_005257.6	c.839G>C	p.Gly280Ala	missense_variant	2/7	ENST00000269216.10
GATA6	XM_047437483.1	c.839G>C	p.Gly280Ala	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA6	ENST00000269216.10	c.839G>C	p.Gly280Ala	missense_variant	2/7	1	NM_005257.6	P1
GATA6	ENST00000581694.1	c.839G>C	p.Gly280Ala	missense_variant	1/6	1		P1

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 31 AN: 150958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000429

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000629 AC: 673 AN: 1070422 Hom.: 0 Cov.: 30 AF XY: 0.000601 AC XY: 304 AN XY: 505766

Gnomad4 AFR exome AF: 0.0000447

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000475

Gnomad4 NFE exome AF: 0.000721

Gnomad4 OTH exome AF: 0.000257

GnomAD4 genome AF: 0.000205 AC: 31 AN: 150958 Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 8 AN XY: 73682

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000429

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000280

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tetralogy of Fallot;C1857586:Conotruncal heart malformations;C3280939:Atrioventricular septal defect 5;C3280943:Atrial septal defect 9;C4012454:Pancreatic hypoplasia-diabetes-congenital heart disease syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2023

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Atrioventricular septal defect 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 280 of the GATA6 protein (p.Gly280Ala). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GATA6-related conditions. ClinVar contains an entry for this variant (Variation ID: 540131). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GATA6 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	18
Dann	Benign	0.92
DEOGEN2	Uncertain	0.65	D;D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.60	N;N
MutationTaster	Benign	0.83	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.090	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.37	T;.
Sift4G	Benign	0.54	T;T
Polyphen		0.74	P;P
Vest4		0.21
MVP		0.96
ClinPred		0.22	T
GERP RS		2.7
Varity_R		0.066
gMVP		0.41

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: rs904519303; hg19: chr18-19751944;