rs994978

Variant names:

• chr4-110631242-T-C
• rs994978
• ENST00000355080.9:c.46+1711A>G

Variant summary

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

The NM_153426.3(PITX2):​c.184+1101A>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 NM_153426.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae)
• Axenfeld-Rieger syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• ring dermoid of cornea

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 = 0.678 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX2	NM_001204397.2		c.184+1101A>G		intron	N/A	NP_001191326.1	Q99697-1
	PITX2	NM_001204398.1		c.184+1101A>G		intron	N/A	NP_001191327.1	Q99697-1
	PITX2	NM_153426.3		c.184+1101A>G		intron	N/A	NP_700475.1	Q99697-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX2	ENST00000355080.9	TSL:1	c.46+1711A>G		intron	N/A	ENSP00000347192.5	Q99697-3
	PITX2	ENST00000354925.6	TSL:2	c.184+1101A>G		intron	N/A	ENSP00000347004.2	Q99697-1
	PITX2	ENST00000394595.8	TSL:5	c.184+1101A>G		intron	N/A	ENSP00000378095.4	Q99697-1

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

African (AFR) AF: 0.477 AC: 19761 AN: 41454

American (AMR) AF: 0.682 AC: 10423 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2485 AN: 3470

East Asian (EAS) AF: 0.488 AC: 2514 AN: 5156

South Asian (SAS) AF: 0.674 AC: 3242 AN: 4812

European-Finnish (FIN) AF: 0.542 AC: 5730 AN: 10570

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.683 AC: 46425 AN: 67988

Other (OTH) AF: 0.620 AC: 1305 AN: 2106

Alfa AF: 0.612 Hom.: 4386

Bravo AF: 0.617

Asia WGS AF: 0.515 AC: 1791 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.15
DANN	Benign	0.45
PhyloP100		-1.7
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: rs994978; hg19: chr4-111552398;