rs146949786

Positions:

• chr18-22183025-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005257.6(GATA6):​c.1602A>G​(p.Thr534=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,612,956 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (21 hom.)
• Consequence: GATA6 NM_005257.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.676

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 18-22183025-A-G is Benign according to our data. Variant chr18-22183025-A-G is described in ClinVar as [Benign]. Clinvar id is 240128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-22183025-A-G is described in Lovd as [Likely_benign]. Variant chr18-22183025-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.676 with no splicing effect.
• BS2: High AC in GnomAd4 at 529 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA6	NM_005257.6	c.1602A>G	p.Thr534=	synonymous_variant	6/7	ENST00000269216.10	NP_005248.2
GATA6	XM_047437483.1	c.1602A>G	p.Thr534=	synonymous_variant	6/7		XP_047293439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA6	ENST00000269216.10	c.1602A>G	p.Thr534=	synonymous_variant	6/7	1	NM_005257.6	ENSP00000269216	P1
GATA6	ENST00000581694.1	c.1602A>G	p.Thr534=	synonymous_variant	5/6	1		ENSP00000462313	P1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00582

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00308 AC: 775 AN: 251412 Hom.: 3 AF XY: 0.00302 AC XY: 410 AN XY: 135886

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00454 AC: 6631 AN: 1460686 Hom.: 21 Cov.: 31 AF XY: 0.00442 AC XY: 3212 AN XY: 726720

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00557

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.00317 AC XY: 236 AN XY: 74464

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00582

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00495 Hom.: 1

Bravo AF: 0.00359

EpiCase AF: 0.00365

EpiControl AF: 0.00474

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	GATA6: BS1, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

Atrioventricular septal defect 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.7
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146949786; hg19: chr18-19762986; COSMIC: COSV52528139; COSMIC: COSV52528139;