18-22172139-A-C

Variant names:

• chr18-22172139-A-C
• rs1223505085
• NM_005257.6:c.995A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005257.6(GATA6):​c.995A>C​(p.His332Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H332R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.91
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• atrial septal defect 9

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, G2P
• atrioventricular septal defect 5

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pancreatic hypoplasia-diabetes-congenital heart disease syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, Genomics England PanelApp
• metabolic syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tetralogy of fallot

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• conotruncal heart malformations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005257.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA6	NM_005257.6	MANE Select	c.995A>C	p.His332Pro	missense	Exon 2 of 7	NP_005248.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA6	ENST00000269216.10	TSL:1 MANE Select	c.995A>C	p.His332Pro	missense	Exon 2 of 7	ENSP00000269216.3	Q92908-1
	GATA6	ENST00000581694.1	TSL:1	c.995A>C	p.His332Pro	missense	Exon 1 of 6	ENSP00000462313.1	Q92908-1
	GATA6	ENST00000853536.1		c.995A>C	p.His332Pro	missense	Exon 2 of 8	ENSP00000523595.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 141584 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000257 AC: 32 AN: 1247092 Hom.: 0 Cov.: 35 AF XY: 0.0000276 AC XY: 17 AN XY: 615378

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000148 AC: 4 AN: 27030

American (AMR) AF: 0.0000317 AC: 1 AN: 31564

Ashkenazi Jewish (ASJ) AF: 0.0000498 AC: 1 AN: 20062

East Asian (EAS) AF: 0.0000399 AC: 1 AN: 25066

South Asian (SAS) AF: 0.00 AC: 0 AN: 76816

European-Finnish (FIN) AF: 0.0000441 AC: 1 AN: 22692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4838

European-Non Finnish (NFE) AF: 0.0000212 AC: 21 AN: 989956

Other (OTH) AF: 0.0000611 AC: 3 AN: 49068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 141584 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 68894

African (AFR) AF: 0.00 AC: 0 AN: 38576

American (AMR) AF: 0.00 AC: 0 AN: 14568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3356

East Asian (EAS) AF: 0.00 AC: 0 AN: 4208

South Asian (SAS) AF: 0.00 AC: 0 AN: 3952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64922

Other (OTH) AF: 0.00 AC: 0 AN: 1996

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.69	N
PhyloP100		2.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.29
Sift	Benign	0.034	D
Sift4G	Uncertain	0.039	D
Polyphen		0.97	D
Vest4		0.48
MutPred		0.36		Gain of glycosylation at H332 (P = 0.0226)
MVP		0.96
ClinPred		0.81	D
GERP RS		-0.11
Varity_R		0.25
gMVP		0.53
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1223505085; hg19: chr18-19752100;