rs1553922891

Variant names:

• chr4-110621213-G-GT
• rs1553922891
• NM_000325.6:c.361dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_000325.6(PITX2):​c.361dupA​(p.Thr121AsnfsTer131) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000653742: This variant is expected to disrupt the functionally conserved OAR or aristaless domain, which is located in the final 39 amino acids of the PITX2 protein. This domain mediates the interaction with a number of proteins that are required for PITX2 transcriptional transactivation activity (PMID:10490637, 18045789, 15728254).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: PITX2 NM_000325.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.20
• Publications: 0 publications found

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]

PITX2 Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Axenfeld-Rieger syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• ring dermoid of cornea

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• aniridia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Axenfeld anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Axenfeld-Rieger syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Rieger anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Peters anomaly

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 45 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000653742: This variant is expected to disrupt the functionally conserved OAR or aristaless domain, which is located in the final 39 amino acids of the PITX2 protein. This domain mediates the interaction with a number of proteins that are required for PITX2 transcriptional transactivation activity (PMID: 10490637, 18045789, 15728254).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-110621213-G-GT is Pathogenic according to our data. Variant chr4-110621213-G-GT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 474010.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000325.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX2	NM_000325.6	MANE Select	c.361dupA	p.Thr121AsnfsTer131	frameshift	Exon 2 of 3	NP_000316.2
	PITX2	NM_001204397.2		c.340dupA	p.Thr114AsnfsTer131	frameshift	Exon 5 of 6	NP_001191326.1	Q99697-1
	PITX2	NM_001204398.1		c.340dupA	p.Thr114AsnfsTer131	frameshift	Exon 4 of 5	NP_001191327.1	Q99697-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX2	ENST00000644743.1	MANE Select	c.361dupA	p.Thr121AsnfsTer131	frameshift	Exon 2 of 3	ENSP00000495061.1	Q99697-2
	PITX2	ENST00000355080.9	TSL:1	c.202dupA	p.Thr68AsnfsTer131	frameshift	Exon 3 of 4	ENSP00000347192.5	Q99697-3
	PITX2	ENST00000354925.6	TSL:2	c.340dupA	p.Thr114AsnfsTer131	frameshift	Exon 6 of 7	ENSP00000347004.2	Q99697-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Anterior segment dysgenesis 4;C3714873:Axenfeld-Rieger syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2

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

Other links and lift over

dbSNP: rs1553922891; hg19: chr4-111542369;