rs1947187

chr4-110624341-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000355080.9(PITX2):c.47-2972G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 151,502 control chromosomes in the GnomAD database, including 8,832 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 0.29 (8832 hom., cov: 33)
• Consequence: PITX2 ENST00000355080.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.271

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITX2	NM_001204397.2	c.185-2972G>A		intron_variant
PITX2	NM_001204398.1	c.185-2972G>A		intron_variant
PITX2	NM_001204399.1	c.47-2972G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITX2	ENST00000355080.9	c.47-2972G>A		intron_variant		1		P1
PITX2	ENST00000354925.6	c.185-2972G>A		intron_variant		2
PITX2	ENST00000394595.8	c.185-2972G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43211 AN: 151384 Hom.: 8798 Cov.: 33

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.264

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

GnomAD4 genome AF: 0.286 AC: 43299 AN: 151502 Hom.: 8832 Cov.: 33 AF XY: 0.283 AC XY: 20981 AN XY: 74080

Gnomad4 AFR AF: 0.583

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.267

Alfa AF: 0.200 Hom.: 2317

Bravo AF: 0.301

Asia WGS AF: 0.331 AC: 1150 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	2.4
Dann	Benign	0.49

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1947187; hg19: chr4-111545497;