10-102230762-C-T

Position:

• chr10-102230762-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005029.4(PITX3):​c.661G>A​(p.Gly221Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: PITX3 NM_005029.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

Genes affected

PITX3 (HGNC:9006): (paired like homeodomain 3) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family act as transcription factors. This protein is involved in lens formation during eye development. Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis and congenital cataracts. [provided by RefSeq, Jul 2008]

GBF1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18420002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITX3	NM_005029.4	c.661G>A	p.Gly221Ser	missense_variant	4/4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1	c.661G>A	p.Gly221Ser	missense_variant	3/3		XP_047281308.1
GBF1	NM_001391923.1	c.-165C>T		5_prime_UTR_variant	1/40		NP_001378852.1
GBF1	NM_001391924.1	c.-303C>T		5_prime_UTR_variant	1/41		NP_001378853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITX3	ENST00000370002.8	c.661G>A	p.Gly221Ser	missense_variant	4/4	1	NM_005029.4	ENSP00000359019	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 29, 2023

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. 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 disruptive. This variant has not been reported in the literature in individuals affected with PITX3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 221 of the PITX3 protein (p.Gly221Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.66	T;.
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.76	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.19
Sift	Benign	0.68	T;T
Sift4G	Benign	0.95	T;T
Polyphen		0.010	B;B
Vest4		0.20
MutPred		0.31		Gain of glycosylation at G221 (P = 7e-04);Gain of glycosylation at G221 (P = 7e-04);
MVP		0.40
MPC		1.7
ClinPred		0.62	D
GERP RS		5.0
Varity_R		0.073
gMVP		0.51

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: rs1377696514; hg19: chr10-103990519;