chr4-110625599-G-A

Variant names:

• chr4-110625599-G-A
• rs17041972
• ENST00000355080.9:c.47-4230C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000355080.9(PITX2):​c.47-4230C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 152,192 control chromosomes in the GnomAD database, including 1,916 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (1916 hom., cov: 33)
• Consequence: PITX2 ENST00000355080.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.879
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX2	NM_001204397.2	c.185-4230C>T		intron_variant	Intron 4 of 5		NP_001191326.1
PITX2	NM_001204398.1	c.185-4230C>T		intron_variant	Intron 3 of 4		NP_001191327.1
PITX2	NM_153426.3	c.185-4230C>T		intron_variant	Intron 3 of 4		NP_700475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000355080.9	c.47-4230C>T		intron_variant	Intron 2 of 3	1		ENSP00000347192.5
PITX2	ENST00000354925.6	c.185-4230C>T		intron_variant	Intron 5 of 6	2		ENSP00000347004.2
PITX2	ENST00000394595.8	c.185-4230C>T		intron_variant	Intron 3 of 4	5		ENSP00000378095.4

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23904 AN: 152074 Hom.: 1916 Cov.: 33

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.157

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.157 AC: 23919 AN: 152192 Hom.: 1916 Cov.: 33 AF XY: 0.157 AC XY: 11666 AN XY: 74412

African (AFR) AF: 0.179 AC: 7416 AN: 41494

American (AMR) AF: 0.146 AC: 2232 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 542 AN: 3470

East Asian (EAS) AF: 0.159 AC: 822 AN: 5184

South Asian (SAS) AF: 0.187 AC: 901 AN: 4820

European-Finnish (FIN) AF: 0.120 AC: 1275 AN: 10594

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10247 AN: 68010

Other (OTH) AF: 0.155 AC: 328 AN: 2114

Alfa AF: 0.153 Hom.: 860

Bravo AF: 0.158

Asia WGS AF: 0.205 AC: 709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.3
DANN	Benign	0.69
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17041972; hg19: chr4-111546755;