rs17554590

Variant names:

• chr4-110641746-C-G
• rs17554590
• NM_001204398.1:c.-11+173G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BS1 BS2

The NM_001204398.1(PITX2):​c.-11+173G>C variant causes a intron change. The variant allele was found at a frequency of 0.0142 in 152,270 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.014 (37 hom., cov: 33)
• Consequence: PITX2 NM_001204398.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.56
• Publications: 2 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.16).
• BP6: Variant 4-110641746-C-G is Benign according to our data. Variant chr4-110641746-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1707318.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0142 (2160/152270) while in subpopulation AMR AF = 0.0203 (311/15294). AF 95% confidence interval is 0.0188. There are 37 homozygotes in GnomAd4. There are 1008 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2160 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204398.1. 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_001204398.1		c.-11+173G>C		intron	N/A	NP_001191327.1	Q99697-1
	PITX2	NM_001204399.1		c.-11+173G>C		intron	N/A	NP_001191328.1	Q99697-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX2	ENST00000354925.6	TSL:2	c.-1619+173G>C		intron	N/A	ENSP00000347004.2	Q99697-1
	PITX2	ENST00000511837.5	TSL:5	c.-11+173G>C		intron	N/A	ENSP00000421454.1	D6RFI4
	PITX2	ENST00000511990.1	TSL:3	c.-11+173G>C		intron	N/A	ENSP00000424142.1	D6RBG8

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2160 AN: 152152 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0187

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

GnomAD4 genome AF: 0.0142 AC: 2160 AN: 152270 Hom.: 37 Cov.: 33 AF XY: 0.0135 AC XY: 1008 AN XY: 74450

African (AFR) AF: 0.00318 AC: 132 AN: 41552

American (AMR) AF: 0.0203 AC: 311 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 189 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1340 AN: 68016

Other (OTH) AF: 0.0185 AC: 39 AN: 2110

Alfa AF: 0.0168 Hom.: 5

Bravo AF: 0.0141

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.78
PhyloP100		5.6
PromoterAI		-0.016	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs17554590; hg19: chr4-111562902;