chr18-22171451-G-A

Variant names:

• chr18-22171451-G-A
• rs749200220
• NM_005257.6:c.307G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005257.6(GATA6):​c.307G>A​(p.Gly103Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,444,016 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G103E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA6	NM_005257.6	c.307G>A	p.Gly103Arg	missense_variant	Exon 2 of 7	ENST00000269216.10	NP_005248.2
GATA6	XM_047437483.1	c.307G>A	p.Gly103Arg	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	c.307G>A	p.Gly103Arg	missense_variant	Exon 2 of 7	1	NM_005257.6	ENSP00000269216.3
GATA6	ENST00000581694.1	c.307G>A	p.Gly103Arg	missense_variant	Exon 1 of 6	1		ENSP00000462313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000458 AC: 1 AN: 218168 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1444016 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718606

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.0000226 AC: 1 AN: 44300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 85680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110162

Other (OTH) AF: 0.00 AC: 0 AN: 60020

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000168 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.68	.;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.81	L;L
PhyloP100		3.0
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.2	N;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.19	T;T
Polyphen		0.44	B;B
Vest4		0.40
MutPred		0.22		Gain of methylation at G103 (P = 0.0875);Gain of methylation at G103 (P = 0.0875);
MVP		0.98
ClinPred		0.63	D
GERP RS		3.0
Varity_R		0.19
gMVP		0.41
Mutation Taster		=81/19	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: rs749200220; hg19: chr18-19751412;