rs886059002

Variant names:

• chr4-110617514-T-C
• rs886059002
• NM_000325.6:c.*611A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000325.6(PITX2):​c.*611A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: PITX2 NM_000325.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:7
• Conservation: PhyloP100: 4.65
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).

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.*611A>G		3_prime_UTR	Exon 3 of 3	NP_000316.2
	PITX2	NM_001204397.2		c.*611A>G		3_prime_UTR	Exon 6 of 6	NP_001191326.1	Q99697-1
	PITX2	NM_001204398.1		c.*611A>G		3_prime_UTR	Exon 5 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.*611A>G		3_prime_UTR	Exon 3 of 3	ENSP00000495061.1	Q99697-2
	PITX2	ENST00000355080.9	TSL:1	c.*611A>G		3_prime_UTR	Exon 4 of 4	ENSP00000347192.5	Q99697-3
	PITX2	ENST00000354925.6	TSL:2	c.*611A>G		3_prime_UTR	Exon 7 of 7	ENSP00000347004.2	Q99697-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33

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 Cov.: 0

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Anterior segment dysgenesis 4 (1)
-	1	-	Axenfeld-Rieger syndrome type 1 (1)
-	1	-	Cataract (1)
-	1	-	Hypoplasia of the iris (1)
-	1	-	Irido-corneo-trabecular dysgenesis (1)
-	1	-	PITX2-Related Eye Abnormalities (1)
-	1	-	Ring dermoid of cornea (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		4.6

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: rs886059002; hg19: chr4-111538670;