NM_000325.6:c.361A>C

Variant names:

• chr4-110621214-T-G
• rs104893858
• NM_000325.6:c.361A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000325.6(PITX2):​c.361A>C​(p.Thr121Pro) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PITX2 NM_000325.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.20
• Publications: 12 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• ring dermoid of cornea

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000325.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 4-110621214-T-G is Pathogenic according to our data. Variant chr4-110621214-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 8085.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX2	NM_000325.6	c.361A>C	p.Thr121Pro	missense_variant	Exon 2 of 3	ENST00000644743.1	NP_000316.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000644743.1	c.361A>C	p.Thr121Pro	missense_variant	Exon 2 of 3		NM_000325.6	ENSP00000495061.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Axenfeld-Rieger syndrome type 1 Pathogenic:1

Dec 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;D;D;.;D;D;D;.;D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	.;D;.;.;.;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;.;M;M;.;M;M;M;.;.;.;.
PhyloP100		6.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.1	.;D;.;D;D;D;.;.;.;D;D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;D;.;D;D;D;.;.;.;D;D;.
Sift4G	Uncertain	0.0040	.;D;.;D;D;D;D;D;D;D;.;D
Polyphen		0.99	D;D;D;D;P;D;D;D;P;D;.;.
Vest4		0.83, 0.86, 0.74, 0.86, 0.85, 0.86, 0.74, 0.54
MutPred		0.69		.;.;Gain of glycosylation at S113 (P = 0.0316);Gain of glycosylation at S113 (P = 0.0316);.;Gain of glycosylation at S113 (P = 0.0316);Gain of glycosylation at S113 (P = 0.0316);Gain of glycosylation at S113 (P = 0.0316);.;Gain of glycosylation at S113 (P = 0.0316);.;.;
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.99
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

Other links and lift over

dbSNP: rs104893858; hg19: chr4-111542370;