18-22171210-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005257.6(GATA6):c.66C>A(p.Ser22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27768734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA6	NM_005257.6	c.66C>A	p.Ser22Arg	missense_variant	2/7	ENST00000269216.10
GATA6	XM_047437483.1	c.66C>A	p.Ser22Arg	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA6	ENST00000269216.10	c.66C>A	p.Ser22Arg	missense_variant	2/7	1	NM_005257.6	P1
GATA6	ENST00000581694.1	c.66C>A	p.Ser22Arg	missense_variant	1/6	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447746 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720784

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2023

Not observed at significant frequency in large population cohorts (gnomAD); 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.90	N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.019	D;.
Sift4G	Benign	0.28	T;T
Polyphen		0.61	P;P
Vest4		0.087
MutPred		0.15		Loss of phosphorylation at S22 (P = 0.0085);Loss of phosphorylation at S22 (P = 0.0085);
MVP		0.92
ClinPred		0.62	D
GERP RS		2.7
Varity_R		0.22
gMVP		0.27

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: rs1266267498; hg19: chr18-19751171;