rs1947187

Variant names:

• chr4-110624341-C-T
• rs1947187
• ENST00000355080.9:c.47-2972G>A

Variant summary

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

The NM_153426.3(PITX2):​c.185-2972G>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 NM_153426.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.271
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153426.3. 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.185-2972G>A		intron	N/A	NP_001191326.1
	PITX2	NM_001204398.1		c.185-2972G>A		intron	N/A	NP_001191327.1
	PITX2	NM_153426.3		c.185-2972G>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.47-2972G>A		intron	N/A	ENSP00000347192.5
	PITX2	ENST00000354925.6	TSL:2	c.185-2972G>A		intron	N/A	ENSP00000347004.2
	PITX2	ENST00000394595.8	TSL:5	c.185-2972G>A		intron	N/A	ENSP00000378095.4

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

African (AFR) AF: 0.583 AC: 24143 AN: 41388

American (AMR) AF: 0.205 AC: 3131 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 590 AN: 3452

East Asian (EAS) AF: 0.258 AC: 1335 AN: 5176

South Asian (SAS) AF: 0.247 AC: 1187 AN: 4806

European-Finnish (FIN) AF: 0.149 AC: 1572 AN: 10566

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10609 AN: 67572

Other (OTH) AF: 0.267 AC: 560 AN: 2100

Alfa AF: 0.200 Hom.: 2578

Bravo AF: 0.301

Asia WGS AF: 0.331 AC: 1150 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.4
DANN	Benign	0.49
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: rs1947187; hg19: chr4-111545497;