Genetic Variant NM_005257.6:c.1631C>T (chr18-22200666-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005257.6(GATA6):c.1631C>T(p.Pro544Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

GATA6
NM_005257.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.70

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:

ENSG00000266283 (HGNC:):

ENSG00000266283 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20006666).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA6	NM_005257.6 link	c.1631C>T	p.Pro544Leu	missense_variant	Exon 7 of 7	ENST00000269216.10	NP_005248.2	Q92908-1
GATA6	XM_047437483.1 link	c.1631C>T	p.Pro544Leu	missense_variant	Exon 7 of 7		XP_047293439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GATA6	ENST00000269216.10 link	c.1631C>T	p.Pro544Leu	missense_variant	Exon 7 of 7	1	NM_005257.6	ENSP00000269216.3	Q92908-1
GATA6	ENST00000581694.1 link	c.1631C>T	p.Pro544Leu	missense_variant	Exon 6 of 6	1		ENSP00000462313.1	Q92908-1
ENSG00000266283	ENST00000583442.1 link	n.723G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251168

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

show subpopulations

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Atrioventricular septal defect 5

Uncertain:1

Oct 17, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs767156756, ExAC 0.002%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GATA6-related disease. This sequence change replaces proline with leucine at codon 544 of the GATA6 protein (p.Pro544Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.43

T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

0.040

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

.;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

0.14

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.3

N;.

REVEL

Uncertain

0.31

Sift

Benign

0.25

T;.

Sift4G

Benign

0.17

T;T

Polyphen

0.19

B;B

Vest4

0.094

MutPred

0.22

Loss of phosphorylation at T547 (P = 0.0714);Loss of phosphorylation at T547 (P = 0.0714);

MVP

0.89

ClinPred

0.26

GERP RS

5.9

Varity_R

0.040

gMVP

0.35

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