18-22171919-G-C

Position:

• chr18-22171919-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005257.6(GATA6):​c.775G>C​(p.Val259Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 1,026,456 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. 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. V259I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.617

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34684706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA6	NM_005257.6	c.775G>C	p.Val259Leu	missense_variant	2/7	ENST00000269216.10
GATA6	XM_047437483.1	c.775G>C	p.Val259Leu	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA6	ENST00000269216.10	c.775G>C	p.Val259Leu	missense_variant	2/7	1	NM_005257.6	P1
GATA6	ENST00000581694.1	c.775G>C	p.Val259Leu	missense_variant	1/6	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000195 AC: 2 AN: 1026456 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 2 AN XY: 483796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000151

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: 0.00000113

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.36	N
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	0.041	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.27
Sift	Benign	0.14	T;.
Sift4G	Benign	0.59	T;T
Polyphen		0.019	B;B
Vest4		0.090
MutPred		0.24		Gain of catalytic residue at S254 (P = 0.1532);Gain of catalytic residue at S254 (P = 0.1532);
MVP		0.94
ClinPred		0.091	T
GERP RS		0.28
Varity_R		0.12
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: rs911752926; hg19: chr18-19751880;