rs143026087

Positions:

• chr18-22181524-C-T

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.1374C>T​(p.Asn458=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,614,158 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (26 hom.)
• Consequence: GATA6 NM_005257.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.761

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=-0.59).
• BP6: Variant 18-22181524-C-T is Benign according to our data. Variant chr18-22181524-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-22181524-C-T is described in Lovd as [Likely_benign]. Variant chr18-22181524-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.761 with no splicing effect.
• BS2: High AC in GnomAd4 at 353 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA6	NM_005257.6	c.1374C>T	p.Asn458=	synonymous_variant	4/7	ENST00000269216.10
GATA6	XM_047437483.1	c.1374C>T	p.Asn458=	synonymous_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA6	ENST00000269216.10	c.1374C>T	p.Asn458=	synonymous_variant	4/7	1	NM_005257.6	P1
GATA6	ENST00000581694.1	c.1374C>T	p.Asn458=	synonymous_variant	3/6	1		P1

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00217 AC: 546 AN: 251484 Hom.: 3 AF XY: 0.00246 AC XY: 334 AN XY: 135916

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00340

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00410 AC: 5991 AN: 1461860 Hom.: 26 Cov.: 32 AF XY: 0.00407 AC XY: 2963 AN XY: 727228

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00486

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74482

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00381

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00311 Hom.: 0

Bravo AF: 0.00225

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GATA6: BP4, BP7, BS1, BS2 -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Tetralogy of Fallot;C1857586:Conotruncal heart malformations;C3280939:Atrioventricular septal defect 5;C3280943:Atrial septal defect 9;C4012454:Pancreatic hypoplasia-diabetes-congenital heart disease syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 28, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Atrioventricular septal defect 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.7
DANN	Benign	0.88

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: rs143026087; hg19: chr18-19761485; COSMIC: COSV52526226; COSMIC: COSV52526226;