18-22171176-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005257.6(GATA6):c.32C>T(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P11P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19053915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA6	NM_005257.6	c.32C>T	p.Pro11Leu	missense_variant	2/7	ENST00000269216.10
GATA6	XM_047437483.1	c.32C>T	p.Pro11Leu	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA6	ENST00000269216.10	c.32C>T	p.Pro11Leu	missense_variant	2/7	1	NM_005257.6	P1
GATA6	ENST00000581694.1	c.32C>T	p.Pro11Leu	missense_variant	1/6	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Invitae

Aug 09, 2021

This sequence change replaces proline with leucine at codon 11 of the GATA6 protein (p.Pro11Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GATA6-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	0.15
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.59	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	-0.090	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	0.89	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;.
REVEL	Benign	0.28
Sift	Benign	0.19	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.11
MutPred		0.31		Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);
MVP		0.92
ClinPred		0.13	T
GERP RS		2.6
Varity_R		0.080
gMVP		0.16

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: rs1598733637; hg19: chr18-19751137;