18-22171167-G-A

Position:

• chr18-22171167-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005257.6(GATA6):​c.23G>A​(p.Trp8Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000138 in 1,447,736 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GATA6 NM_005257.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.44

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-22171167-G-A is Pathogenic according to our data. Variant chr18-22171167-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 977802.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA6	NM_005257.6	c.23G>A	p.Trp8Ter	stop_gained	2/7	ENST00000269216.10	NP_005248.2
GATA6	XM_047437483.1	c.23G>A	p.Trp8Ter	stop_gained	2/7		XP_047293439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA6	ENST00000269216.10	c.23G>A	p.Trp8Ter	stop_gained	2/7	1	NM_005257.6	ENSP00000269216	P1
GATA6	ENST00000581694.1	c.23G>A	p.Trp8Ter	stop_gained	1/6	1		ENSP00000462313	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447736 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720780

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tetralogy of Fallot Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A
Vest4		0.79
GERP RS		3.7

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: rs2033033528; hg19: chr18-19751128;