18-22171995-C-A

Position:

• chr18-22171995-C-A

Variant summary

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

The NM_005257.6(GATA6):​c.851C>A​(p.Ala284Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000733 in 1,228,334 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.36

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=0.32598907).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA6	NM_005257.6	c.851C>A	p.Ala284Glu	missense_variant	2/7	ENST00000269216.10	NP_005248.2
GATA6	XM_047437483.1	c.851C>A	p.Ala284Glu	missense_variant	2/7		XP_047293439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA6	ENST00000269216.10	c.851C>A	p.Ala284Glu	missense_variant	2/7	1	NM_005257.6	ENSP00000269216	P1
GATA6	ENST00000581694.1	c.851C>A	p.Ala284Glu	missense_variant	1/6	1		ENSP00000462313	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000650 AC: 7 AN: 1077310 Hom.: 0 Cov.: 30 AF XY: 0.00000393 AC XY: 2 AN XY: 509368

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: 0.0000472

Gnomad4 NFE exome AF: 0.00000653

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151024 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73702

Gnomad4 AFR AF: 0.00

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: 0.0000296

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2021

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

Atrioventricular septal defect 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2023

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 284 of the GATA6 protein (p.Ala284Glu). This variant is not present in population databases (gnomAD no frequency). 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: 1314118). 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. 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.80	D;D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.47	.;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.048	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.52	N;.
REVEL	Benign	0.28
Sift	Uncertain	0.028	D;.
Sift4G	Uncertain	0.035	D;D
Polyphen		0.018	B;B
Vest4		0.30
MutPred		0.24		Loss of catalytic residue at A285 (P = 0.2723);Loss of catalytic residue at A285 (P = 0.2723);
MVP		0.79
ClinPred		0.068	T
GERP RS		-0.31
Varity_R		0.086
gMVP		0.29

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: rs185325359; hg19: chr18-19751956;