chr10-102230761-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005029.4(PITX3):c.662G>C(p.Gly221Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,492,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G221S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

PITX3
NM_005029.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0520

Variant links:

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]

PITX3 links:

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]

GBF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.091732025).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PITX3	NM_005029.4 link	c.662G>C	p.Gly221Ala	missense_variant	Exon 4 of 4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1 link	c.662G>C	p.Gly221Ala	missense_variant	Exon 3 of 3		XP_047281308.1
GBF1	NM_001391923.1 link	c.-166C>G		5_prime_UTR_variant	Exon 1 of 40		NP_001378852.1
GBF1	NM_001391924.1 link	c.-304C>G		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 link	c.662G>C	p.Gly221Ala	missense_variant	Exon 4 of 4	1	NM_005029.4	ENSP00000359019.3		O75364

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151688

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

90402

Hom.:

AF XY:

0.00

AC XY:

AN XY:

50120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000143

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000159

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000418

AC:

AN:

1340680

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

659972

show subpopulations

Gnomad4 AFR exome

AF:

0.0000743

Gnomad4 AMR exome

AF:

0.000119

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000308

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.000181

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151688

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74098

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PITX3: PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.59

DANN

Benign

0.80

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.55

T;.

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.092

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.29

N;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.030

N;N

REVEL

Benign

0.17

Sift

Benign

0.56

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.0010

B;B

Vest4

0.14

MutPred

0.33

Loss of catalytic residue at G221 (P = 0.0637);Loss of catalytic residue at G221 (P = 0.0637);

MVP

0.20

MPC

1.8

ClinPred

0.031

GERP RS

0.52

Varity_R

0.026

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over