rs121909248

Positions:

• chr4-110621166-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000325.6(PITX2):​c.409C>T​(p.Arg137Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PITX2 NM_000325.6 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.336

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 7 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 4-110621166-G-A is Pathogenic according to our data. Variant chr4-110621166-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8089.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.409C>T	p.Arg137Trp	missense_variant, splice_region_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.409C>T	p.Arg137Trp	missense_variant, splice_region_variant	2/3		NM_000325.6	ENSP00000495061

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Anterior segment dysgenesis Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Eye Genetics Research Group, Children's Medical Research Institute

Mar 31, 2020

- -

Anterior segment dysgenesis 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;D;D;.;D;D;D;.;D;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	.;.;L;L;.;L;L;L;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-7.3	.;D;.;D;D;D;.;.;.;D;D;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	.;D;.;D;D;D;.;.;.;D;D;.
Sift4G	Pathogenic	0.0	.;D;.;D;D;D;D;D;D;D;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.;.
Vest4		0.87, 0.88, 0.85, 0.88, 0.88, 0.88, 0.85, 0.78
MutPred		0.66		.;.;Loss of disorder (P = 0.0418);Loss of disorder (P = 0.0418);.;Loss of disorder (P = 0.0418);Loss of disorder (P = 0.0418);Loss of disorder (P = 0.0418);.;Loss of disorder (P = 0.0418);.;.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
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: rs121909248; hg19: chr4-111542322; COSMIC: COSV60742306; COSMIC: COSV60742306;