rs17554590

chr4-110641746-C-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2160 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITX2	NM_001204398.1	c.-11+173G>C		intron_variant
PITX2	NM_001204399.1	c.-11+173G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITX2	ENST00000354925.6	c.-1619+173G>C		intron_variant		2
PITX2	ENST00000511837.5	c.-11+173G>C		intron_variant		5
PITX2	ENST00000511990.1	c.-11+173G>C		intron_variant		3

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

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.0545

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0168 Hom.: 5

Bravo AF: 0.0141

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17554590; hg19: chr4-111562902;