chr4-110618690-T-C

Variant names:

• chr4-110618690-T-C
• rs1553922583
• NM_000325.6:c.412-2A>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000325.6(PITX2):​c.412-2A>G variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PITX2 NM_000325.6 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.27

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 1.2984616 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-110618690-T-C is Pathogenic according to our data. Variant chr4-110618690-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 474011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX2	NM_000325.6	c.412-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 2	ENST00000644743.1	NP_000316.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000644743.1	c.412-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 2		NM_000325.6	ENSP00000495061.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Axenfeld-Rieger syndrome type 1 Pathogenic:1

Jun 23, 2022

Human Developmental Genetics Laboratory, Medical College of Wisconsin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Anterior segment dysgenesis 4;C3714873:Axenfeld-Rieger syndrome type 1 Pathogenic:1

Oct 27, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel splice site variant that is expected to disrupt an important protein binding domain. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is expected to disrupt the functionally conserved OAR or aristaless domain, which is located in the final 39 amino acids of the PITX2 protein. This domain mediates the interaction with a number of proteins that are required for PITX2 transcriptional transactivation activity (PMID: 10490637, 18045789, 15728254). In addition, a different variant affecting this splice acceptor site (c.253-1G>A) has been reported in 2 individuals affected with Axenfeld-Rieger syndrome (PMID: 22569110). This suggests that this splice site is critical for PITX2 protein function, and that other variants that affect this splice site may also be pathogenic. This variant has not been reported in the literature in individuals with a PITX2-related disease. This sequence change affects an acceptor splice site in the last intron (intron 4) of the PITX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 187 amino acids of the PITX2 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	37
DANN	Uncertain	0.98
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.78		Position offset: -14
DS_AL_spliceai		0.99		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553922583; hg19: chr4-111539846;