rs185325359

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A284G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

GATA6
NM_005257.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.36

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	UniProt
GATA6	NM_005257.6 linkuse as main transcript	c.851C>A	p.Ala284Glu	missense_variant	2/7	ENST00000269216.10
GATA6	XM_047437483.1 linkuse as main transcript	c.851C>A	p.Ala284Glu	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA6	ENST00000269216.10 linkuse as main transcript	c.851C>A	p.Ala284Glu	missense_variant	2/7	1	NM_005257.6	P1	Q92908-1
GATA6	ENST00000581694.1 linkuse as main transcript	c.851C>A	p.Ala284Glu	missense_variant	1/6	1		P1	Q92908-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151024

Hom.:

Cov.:

show subpopulations

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:

AN:

1077310

Hom.:

Cov.:

AF XY:

0.00000393

AC XY:

AN XY:

509368

show subpopulations

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:

AN:

151024

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73702

show subpopulations

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

LINK: link

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

Invitae

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

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.80

D;D

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.47

.;T

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.33

T;T

MetaSVM

Uncertain

0.048

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.89

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over