Variant 10-102230741-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005029.4(PITX3):c.682G>A(p.Ala228Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000269 in 1,486,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

PITX3
NM_005029.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.88

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:):

GBF1 links:

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ACMG classification

Classification made for transcript

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=0.14680025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PITX3	NM_005029.4 linkuse as main transcript	c.682G>A	p.Ala228Thr	missense_variant	4/4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1 linkuse as main transcript	c.682G>A	p.Ala228Thr	missense_variant	3/3		XP_047281308.1
GBF1	NM_001391923.1 linkuse as main transcript	c.-186C>T		5_prime_UTR_variant	1/40		NP_001378852.1
GBF1	NM_001391924.1 linkuse as main transcript	c.-324C>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 linkuse as main transcript	c.682G>A	p.Ala228Thr	missense_variant	4/4	1	NM_005029.4	ENSP00000359019	P1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151804

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000225

AC:

AN:

1334476

Hom.:

Cov.:

AF XY:

0.00000305

AC XY:

AN XY:

656248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000285

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151804

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

0.029

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.70

T;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.52

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.57

N;N

REVEL

Benign

0.21

Sift

Benign

0.31

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0010

B;B

Vest4

0.32

MutPred

0.23

Gain of glycosylation at A228 (P = 0.0015);Gain of glycosylation at A228 (P = 0.0015);

MVP

0.46

MPC

1.2

ClinPred

0.85

GERP RS

5.0

Varity_R

0.15

gMVP

0.52

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over