rs387906814

Positions:

• chr18-22171736-C-A
• chr18-22171736-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005257.6(GATA6):​c.592C>A​(p.Leu198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000759 in 1,317,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L198V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA6	NM_005257.6	c.592C>A	p.Leu198Met	missense_variant	2/7	ENST00000269216.10	NP_005248.2
GATA6	XM_047437483.1	c.592C>A	p.Leu198Met	missense_variant	2/7		XP_047293439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA6	ENST00000269216.10	c.592C>A	p.Leu198Met	missense_variant	2/7	1	NM_005257.6	ENSP00000269216.3
GATA6	ENST00000581694.1	c.592C>A	p.Leu198Met	missense_variant	1/6	1		ENSP00000462313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.59e-7 AC: 1 AN: 1317234 Hom.: 0 Cov.: 30 AF XY: 0.00000154 AC XY: 1 AN XY: 650502

Gnomad4 AFR exome AF: 0.00

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: 0.0000300

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrioventricular septal defect 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 23, 2022

This variant has not been reported in the literature in individuals affected with GATA6-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1373961). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 198 of the GATA6 protein (p.Leu198Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.66	.;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-0.83	N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0050	D;.
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;D
Vest4		0.37
MutPred		0.62		Loss of catalytic residue at L198 (P = 8e-04);Loss of catalytic residue at L198 (P = 8e-04);
MVP		0.97
ClinPred		0.81	D
GERP RS		2.7
Varity_R		0.35
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-19751697;