rs2595098

Variant names:

• chr4-110642326-T-A
• rs2595098
• ENST00000730951.1:n.166T>A

Variant summary

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

The ENST00000730951.1(ENSG00000295560):​n.166T>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 152,288 control chromosomes in the GnomAD database, including 159 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 0.040 (159 hom., cov: 33)
• Consequence: ENSG00000295560 ENST00000730951.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.719
• Publications: 3 publications found

Genes affected

ENSG00000295560 (HGNC:):

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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX2	NM_001204398.1	c.-418A>T		upstream_gene_variant			NP_001191327.1
PITX2	NM_001204399.1	c.-418A>T		upstream_gene_variant			NP_001191328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000295560	ENST00000730951.1	n.166T>A		non_coding_transcript_exon_variant	Exon 1 of 4
PITX2	ENST00000511837.5	c.-418A>T		upstream_gene_variant		5		ENSP00000421454.1

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6094 AN: 152172 Hom.: 159 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0666

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0629

Gnomad OTH AF: 0.0377

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

GnomAD4 genome AF: 0.0400 AC: 6091 AN: 152288 Hom.: 159 Cov.: 33 AF XY: 0.0385 AC XY: 2864 AN XY: 74462

African (AFR) AF: 0.0110 AC: 457 AN: 41570

American (AMR) AF: 0.0281 AC: 430 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4826

European-Finnish (FIN) AF: 0.0666 AC: 706 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0629 AC: 4277 AN: 68014

Other (OTH) AF: 0.0373 AC: 79 AN: 2116

Alfa AF: 0.0429 Hom.: 21

Bravo AF: 0.0369

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.30
DANN	Benign	0.42
PhyloP100		-0.72
PromoterAI		-0.015	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2595098; hg19: chr4-111563482;