rs387906815

chr18-22171677-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005257.6(GATA6):c.533C>T(p.Ala178Val) variant causes a missense change. The variant allele was found at a frequency of 0.00014 in 1,499,588 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A178A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (2 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 4.73

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0135444105).
• BP6: Variant 18-22171677-C-T is Benign according to our data. Variant chr18-22171677-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 30209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA6	NM_005257.6	c.533C>T	p.Ala178Val	missense_variant	2/7	ENST00000269216.10
GATA6	XM_047437483.1	c.533C>T	p.Ala178Val	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA6	ENST00000269216.10	c.533C>T	p.Ala178Val	missense_variant	2/7	1	NM_005257.6	P1
GATA6	ENST00000581694.1	c.533C>T	p.Ala178Val	missense_variant	1/6	1		P1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 124 AN: 151060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000296

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000180 AC: 18 AN: 100036 Hom.: 3 AF XY: 0.000158 AC XY: 9 AN XY: 56836

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.000114

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000638 AC: 86 AN: 1348416 Hom.: 2 Cov.: 30 AF XY: 0.0000645 AC XY: 43 AN XY: 666200

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.0000700

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: 0.00000188

Gnomad4 OTH exome AF: 0.000143

GnomAD4 genome AF: 0.000820 AC: 124 AN: 151172 Hom.: 0 Cov.: 32 AF XY: 0.000663 AC XY: 49 AN XY: 73862

Gnomad4 AFR AF: 0.00285

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.0455 Hom.: 330

Bravo AF: 0.000850

ExAC AF: 0.000321 AC: 17

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrioventricular septal defect 5 Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2010	- -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 26, 2018

ACMG criteria: PP3 (6 predictors), BP4 (4 predictors), BS1 (1.01% in ExAC African pop.), BS2 (2 homozyotes and 34 hets for dominant condition)=benign -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 20, 2021

This variant is associated with the following publications: (PMID: 20581743) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Benign	-0.043
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.62	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.70	N;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.029	D;D
Polyphen		0.99	D;D
Vest4		0.77
MutPred		0.44		Gain of catalytic residue at A178 (P = 0.0275);Gain of catalytic residue at A178 (P = 0.0275);
MVP		0.94
ClinPred		0.18	T
GERP RS		2.4
Varity_R		0.26
gMVP		0.32

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: rs387906815; hg19: chr18-19751638;