rs6533526

Positions:

• chr4-110617671-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 3.52

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]

ACMG classification

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
PITX2	NM_000325.6	c.*454C>T		3_prime_UTR_variant	3/3	ENST00000644743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITX2	ENST00000644743.1	c.*454C>T		3_prime_UTR_variant	3/3		NM_000325.6

Frequencies

GnomAD3 genomes AF: 0.0478 AC: 7265 AN: 152056 Hom.: 543 Cov.: 33

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

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

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:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	This variant is associated with the following publications: (PMID: 15378534) -
Pathogenic, no assertion criteria provided	not provided	Human Genetics School of Medicine of Albacete, Castilla-La Mancha University	-	- -

Axenfeld-Rieger syndrome type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypoplasia of the iris Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This 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

Other links and lift over

dbSNP: rs6533526; hg19: chr4-111538827;