rs6533526

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000325.6(PITX2):​c.*454C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 182,358 control chromosomes in the GnomAD database, including 553 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.048 ( 547 hom., cov: 33)
Exomes 𝑓: 0.0045 ( 6 hom. )

Consequence

PITX2
NM_000325.6 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: 3.52
Variant links:
Genes affected
PITX2 (HGNC:9005): (paired like homeodomain 2) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. The encoded protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes, is involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. Mutations in this gene are associated with Axenfeld-Rieger syndrome, iridogoniodysgenesis syndrome, and sporadic cases of Peters anomaly. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.37).
BP6
Variant 4-110617671-G-A is Benign according to our data. Variant chr4-110617671-G-A is described in ClinVar as [Benign]. Clinvar id is 183253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PITX2NM_000325.6 linkuse as main transcriptc.*454C>T 3_prime_UTR_variant 3/3 ENST00000644743.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PITX2ENST00000644743.1 linkuse as main transcriptc.*454C>T 3_prime_UTR_variant 3/3 NM_000325.6 Q99697-2

Frequencies

GnomAD3 genomes
AF:
0.0478
AC:
7265
AN:
152056
Hom.:
543
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.159
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0272
Gnomad ASJ
AF:
0.0147
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.00182
Gnomad OTH
AF:
0.0464
GnomAD4 exome
AF:
0.00454
AC:
137
AN:
30184
Hom.:
6
Cov.:
0
AF XY:
0.00400
AC XY:
62
AN XY:
15482
show subpopulations
Gnomad4 AFR exome
AF:
0.126
Gnomad4 AMR exome
AF:
0.0144
Gnomad4 ASJ exome
AF:
0.00712
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000537
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00108
Gnomad4 OTH exome
AF:
0.00925
GnomAD4 genome
AF:
0.0479
AC:
7284
AN:
152174
Hom.:
547
Cov.:
33
AF XY:
0.0459
AC XY:
3412
AN XY:
74398
show subpopulations
Gnomad4 AFR
AF:
0.159
Gnomad4 AMR
AF:
0.0271
Gnomad4 ASJ
AF:
0.0147
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.00182
Gnomad4 OTH
AF:
0.0459
Alfa
AF:
0.0119
Hom.:
97
Bravo
AF:
0.0558
Asia WGS
AF:
0.0110
AC:
39
AN:
3474

ClinVar

Significance: Benign
Submissions summary: Pathogenic:1Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMay 14, 2021This variant is associated with the following publications: (PMID: 15378534) -
Pathogenic, no assertion criteria providednot providedHuman Genetics School of Medicine of Albacete, Castilla-La Mancha University-- -
Axenfeld-Rieger syndrome type 1 Benign:2
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
PITX2-Related Eye Abnormalities Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Ring dermoid of cornea Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Cataract Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Irido-corneo-trabecular dysgenesis Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Anterior segment dysgenesis 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Hypoplasia of the iris Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.37
CADD
Benign
17
DANN
Benign
0.92

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.

Other links and lift over

dbSNP: rs6533526; hg19: chr4-111538827; API