4-110629565-G-T

Variant names:

• chr4-110629565-G-T
• rs976568
• ENST00000355080.9:c.46+3388C>A

Variant summary

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

The ENST00000355080.9(PITX2):​c.46+3388C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 152,024 control chromosomes in the GnomAD database, including 25,867 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 0.57 (25867 hom., cov: 33)
• Consequence: PITX2 ENST00000355080.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355080.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX2	NM_001204397.2		c.184+2778C>A		intron	N/A	NP_001191326.1
	PITX2	NM_001204398.1		c.184+2778C>A		intron	N/A	NP_001191327.1
	PITX2	NM_153426.3		c.184+2778C>A		intron	N/A	NP_700475.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX2	ENST00000355080.9	TSL:1	c.46+3388C>A		intron	N/A	ENSP00000347192.5
	PITX2	ENST00000354925.6	TSL:2	c.184+2778C>A		intron	N/A	ENSP00000347004.2
	PITX2	ENST00000394595.8	TSL:5	c.184+2778C>A		intron	N/A	ENSP00000378095.4

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87346 AN: 151906 Hom.: 25853 Cov.: 33

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.587

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

GnomAD4 genome AF: 0.575 AC: 87387 AN: 152024 Hom.: 25867 Cov.: 33 AF XY: 0.573 AC XY: 42593 AN XY: 74312

African (AFR) AF: 0.431 AC: 17869 AN: 41476

American (AMR) AF: 0.645 AC: 9862 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2333 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2460 AN: 5116

South Asian (SAS) AF: 0.667 AC: 3218 AN: 4828

European-Finnish (FIN) AF: 0.582 AC: 6154 AN: 10574

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43420 AN: 67962

Other (OTH) AF: 0.586 AC: 1235 AN: 2108

Alfa AF: 0.626 Hom.: 18017

Bravo AF: 0.574

Asia WGS AF: 0.505 AC: 1757 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.81
PhyloP100		-0.27
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: rs976568; hg19: chr4-111550721;