rs994978

Positions:

• chr4-110631242-T-C

Variant summary

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

The ENST00000355080.9(PITX2):​c.46+1711A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 152,032 control chromosomes in the GnomAD database, including 29,114 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 0.61 (29114 hom., cov: 32)
• Consequence: PITX2 ENST00000355080.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69

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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITX2	NM_001204397.2	c.184+1101A>G		intron_variant
PITX2	NM_001204398.1	c.184+1101A>G		intron_variant
PITX2	NM_001204399.1	c.46+1711A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITX2	ENST00000355080.9	c.46+1711A>G		intron_variant		1		P1
PITX2	ENST00000354925.6	c.184+1101A>G		intron_variant		2
PITX2	ENST00000394595.8	c.184+1101A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92743 AN: 151912 Hom.: 29100 Cov.: 32

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.621

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

GnomAD4 genome AF: 0.610 AC: 92787 AN: 152032 Hom.: 29114 Cov.: 32 AF XY: 0.603 AC XY: 44849 AN XY: 74322

Gnomad4 AFR AF: 0.477

Gnomad4 AMR AF: 0.682

Gnomad4 ASJ AF: 0.716

Gnomad4 EAS AF: 0.488

Gnomad4 SAS AF: 0.674

Gnomad4 FIN AF: 0.542

Gnomad4 NFE AF: 0.683

Gnomad4 OTH AF: 0.620

Alfa AF: 0.617 Hom.: 4299

Bravo AF: 0.617

Asia WGS AF: 0.515 AC: 1791 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.15
DANN	Benign	0.45

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs994978; hg19: chr4-111552398;