rs1205923643

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_005257.6(GATA6):c.1223A>G(p.His408Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000444 in 1,577,806 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

GATA6
NM_005257.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.11

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA6	NM_005257.6 link	c.1223A>G	p.His408Arg	missense_variant	Exon 3 of 7	ENST00000269216.10	NP_005248.2	Q92908-1
GATA6	XM_047437483.1 link	c.1223A>G	p.His408Arg	missense_variant	Exon 3 of 7		XP_047293439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA6	ENST00000269216.10 link	c.1223A>G	p.His408Arg	missense_variant	Exon 3 of 7	1	NM_005257.6	ENSP00000269216.3		Q92908-1
GATA6	ENST00000581694.1 link	c.1223A>G	p.His408Arg	missense_variant	Exon 2 of 6	1		ENSP00000462313.1		Q92908-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000537

AC:

AN:

186356

Hom.:

AF XY:

0.00

AC XY:

AN XY:

102026

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000343

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1425670

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

706398

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.0000497

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.13e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Atrioventricular septal defect 5

Uncertain:1

Nov 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 408 of the GATA6 protein (p.His408Arg). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 540137). 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 expected to disrupt GATA6 protein function with a positive predictive value of 80%. 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

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Benign

0.071

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

.;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.4

L;L

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.2

D;.

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.13

B;B

Vest4

0.67

MutPred

0.65

Gain of MoRF binding (P = 0.035);Gain of MoRF binding (P = 0.035);

MVP

0.96

ClinPred

0.99

GERP RS

3.8

Varity_R

0.89

gMVP

0.76

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