rs104893862

Variant names:

• chr4-110621231-C-T
• rs104893862
• NM_000325.6:c.344G>A
• PITX2 p.Arg115His

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000325.6(PITX2):​c.344G>A​(p.Arg115His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005863063: Experimental studies have shown that this missense change affects PITX2 function (PMID:21052876, 22224469, 27013732).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: PITX2 NM_000325.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.10
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P
• Axenfeld-Rieger syndrome type 1

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

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005863063: Experimental studies have shown that this missense change affects PITX2 function (PMID: 21052876, 22224469, 27013732).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_000325.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 4-110621231-C-T is Pathogenic according to our data. Variant chr4-110621231-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.344G>A	p.Arg115His	missense	Exon 2 of 3	NP_000316.2
	PITX2	NM_001204397.2		c.323G>A	p.Arg108His	missense	Exon 5 of 6	NP_001191326.1	Q99697-1
	PITX2	NM_001204398.1		c.323G>A	p.Arg108His	missense	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.344G>A	p.Arg115His	missense	Exon 2 of 3	ENSP00000495061.1	Q99697-2
	PITX2	ENST00000355080.9	TSL:1	c.185G>A	p.Arg62His	missense	Exon 3 of 4	ENSP00000347192.5	Q99697-3
	PITX2	ENST00000354925.6	TSL:2	c.323G>A	p.Arg108His	missense	Exon 6 of 7	ENSP00000347004.2	Q99697-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Anterior segment dysgenesis (1)
1	-	-	Anterior segment dysgenesis 4;C3714873:Axenfeld-Rieger syndrome type 1 (1)
1	-	-	Axenfeld-Rieger syndrome type 1 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Ring dermoid of cornea (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Benign	0.011
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.010	N
PhyloP100		6.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.84
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104893862;

hg19: chr4-111542387;