NM_005257.6:c.1024G>C

Variant names:

• chr18-22172168-G-C
• rs1468414837
• NM_005257.6:c.1024G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005257.6(GATA6):​c.1024G>C​(p.Gly342Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000362 in 1,381,466 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G342E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• atrial septal defect 9

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics
• atrioventricular septal defect 5

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pancreatic hypoplasia-diabetes-congenital heart disease syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• metabolic syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tetralogy of fallot

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• conotruncal heart malformations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005257.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA6	NM_005257.6	MANE Select	c.1024G>C	p.Gly342Arg	missense	Exon 2 of 7	NP_005248.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA6	ENST00000269216.10	TSL:1 MANE Select	c.1024G>C	p.Gly342Arg	missense	Exon 2 of 7	ENSP00000269216.3
	GATA6	ENST00000581694.1	TSL:1	c.1024G>C	p.Gly342Arg	missense	Exon 1 of 6	ENSP00000462313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000362 AC: 5 AN: 1381466 Hom.: 0 Cov.: 35 AF XY: 0.00000440 AC XY: 3 AN XY: 681626

African (AFR) AF: 0.00 AC: 0 AN: 31390

American (AMR) AF: 0.00 AC: 0 AN: 35614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25048

East Asian (EAS) AF: 0.00 AC: 0 AN: 35632

South Asian (SAS) AF: 0.00 AC: 0 AN: 79064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1077868

Other (OTH) AF: 0.00 AC: 0 AN: 57788

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

Dec 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 342 of the GATA6 protein (p.Gly342Arg). 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: 540132). 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 with a negative 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.016	D
Polyphen		0.40	B
Vest4		0.53
MutPred		0.51		Loss of catalytic residue at V341 (P = 0.0628)
MVP		0.97
ClinPred		0.97	D
GERP RS		2.5
Varity_R		0.27
gMVP		0.64
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1468414837; hg19: chr18-19752129;