rs104893857

Positions:

• chr4-110621255-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000325.6(PITX2):​c.320T>A​(p.Leu107Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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: 9.24

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity PITX2_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000325.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 4-110621255-A-T is Pathogenic according to our data. Variant chr4-110621255-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 8083.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITX2	NM_000325.6	c.320T>A	p.Leu107Gln	missense_variant	2/3	ENST00000644743.1	NP_000316.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000644743.1	c.320T>A	p.Leu107Gln	missense_variant	2/3		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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;D;.;D;D;D;.;D;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.5	.;.;H;H;.;H;H;H;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.6	.;D;.;D;D;D;.;.;.;D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;.;D;D;D;.;.;.;D;D;.
Sift4G	Uncertain	0.0020	.;D;.;D;D;D;D;D;D;D;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.;.
Vest4		0.99, 0.99, 0.98, 0.88
MutPred		0.92		.;.;Gain of disorder (P = 0.0512);Gain of disorder (P = 0.0512);.;Gain of disorder (P = 0.0512);Gain of disorder (P = 0.0512);Gain of disorder (P = 0.0512);.;Gain of disorder (P = 0.0512);.;.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		1.0

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: rs104893857; hg19: chr4-111542411;