18-22171415-C-T

Position:

chr18-22171415-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005257.6(GATA6):c.271C>T(p.Pro91Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,589,650 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

GATA6
NM_005257.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.523

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15470254).

BP6

Variant 18-22171415-C-T is Benign according to our data. Variant chr18-22171415-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404061.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr18-22171415-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA6	NM_005257.6 link	c.271C>T	p.Pro91Ser	missense_variant	2/7	ENST00000269216.10	NP_005248.2	Q92908-1
GATA6	XM_047437483.1 link	c.271C>T	p.Pro91Ser	missense_variant	2/7		XP_047293439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA6	ENST00000269216.10 link	c.271C>T	p.Pro91Ser	missense_variant	2/7	1	NM_005257.6	ENSP00000269216.3		Q92908-1
GATA6	ENST00000581694.1 link	c.271C>T	p.Pro91Ser	missense_variant	1/6	1		ENSP00000462313.1		Q92908-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000112

AC:

AN:

204928

Hom.:

AF XY:

0.000122

AC XY:

AN XY:

114480

show subpopulations

Gnomad AFR exome

AF:

0.000174

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000254

AC:

365

AN:

1437580

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

179

AN XY:

714800

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

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:

0.0000266

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000171

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.0000768

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pancreatic hypoplasia-diabetes-congenital heart disease syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Apr 07, 2023	This sequence variant is a single nucleotide substitution (C>T) at coding position 271 of the GATA6 gene that results in a proline to serine amino acid change at residue 91 of the GATA6 protein. This is a previously reported variant (ClinVar) that has been observed in an individual affected by atrial fibrillation (PMID: 27756709). This variant is present in 29 of 236,226 (0.01%) alleles gnomAD population database. Multiple bioinformatic tools provide conflicting predictions concerning the effect of this variant, and the proline residue at this position is moderately conserved across the vertebrate species examined. A transactivation study found that this variant increases the expression of some, but not all, of GATA6's downstream targets (PMID: 27756709). At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2023

Identified in a patient with early-onset atrial fibrillation (Tucker et al., 2017); Published in vitro functional studies suggest this variant results in increased expression of GATA6 target genes, NPPA and aMHC (Tucker et al., 2017); however, additional studies are needed to clarify the effect of this variant in vivo; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27756709) -

Atrioventricular septal defect 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 91 of the GATA6 protein (p.Pro91Ser). This variant is present in population databases (rs766886560, gnomAD 0.02%). This missense change has been observed in individual(s) with early onset atrial fibrillation or thoracic aortic aneurysm (PMID: 27756709, 28659821). ClinVar contains an entry for this variant (Variation ID: 404061). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GATA6 function (PMID: 27756709). 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 13, 2023

Variant summary: GATA6 c.271C>T (p.Pro91Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 204928 control chromosomes. The observed variant frequency is approximately 180 fold of the estimated maximal expected allele frequency for a pathogenic variant in GATA6 causing Pancreatic Agenesis and Congenital Heart Defects phenotype (6.3e-07), strongly suggesting that the variant is benign. c.271C>T has been reported in the literature in an individual with early-onset atrial fibrillation (Tucker_2017) and in a bicuspid aortic valve/thoracic aortic aneurysm patient cohort (Gillis_2017). However, these reports did not provide strong evidence for causality (e.g. co-segregation data) and therefore do not allow conclusions about association of the variant with Pancreatic Agenesis and Congenital Heart Defects. At least one publication reports experimental evidence evaluating an impact on protein function, finding the variant leads to increased transcriptional activity (Tucker_2017), however, these findings do not allow convincing conclusions about the variant effect. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as likely benign (n=1) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.69

.;T

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.15

T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

0.34

N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.6

N;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0070

D;.

Sift4G

Benign

0.27

T;T

Polyphen

0.0070

B;B

Vest4

0.14

MutPred

0.13

Gain of glycosylation at P91 (P = 0.0154);Gain of glycosylation at P91 (P = 0.0154);

MVP

0.88

ClinPred

0.084

GERP RS

1.6

Varity_R

0.087

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over