10-102230762-C-T

Variant names:

• chr10-102230762-C-T
• rs1377696514
• NM_005029.4:c.661G>A

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:4181): (golgi brefeldin A resistant guanine nucleotide exchange factor 1) This gene encodes a member of the Sec7 domain family. The encoded protein is a guanine nucleotide exchange factor that regulates the recruitment of proteins to membranes by mediating GDP to GTP exchange. The encoded protein is localized to the Golgi apparatus and plays a role in vesicular trafficking by activating ADP ribosylation factor 1. The encoded protein has also been identified as an important host factor for viral replication. Multiple transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

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 rank	MANE	Protein	UniProt
PITX3	NM_005029.4	c.661G>A	p.Gly221Ser	missense_variant	Exon 4 of 4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1	c.661G>A	p.Gly221Ser	missense_variant	Exon 3 of 3		XP_047281308.1
GBF1	NM_001391923.1	c.-165C>T		5_prime_UTR_variant	Exon 1 of 40		NP_001378852.1
GBF1	NM_001391924.1	c.-303C>T		5_prime_UTR_variant	Exon 1 of 41		NP_001378853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX3	ENST00000370002.8	c.661G>A	p.Gly221Ser	missense_variant	Exon 4 of 4	1	NM_005029.4	ENSP00000359019.3

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

Jul 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PITX3-related conditions. 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. -

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
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;