rs17041968

Positions:

• chr4-110623439-T-A
• chr4-110623439-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000355080.9(PITX2):​c.47-2070A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,122 control chromosomes in the GnomAD database, including 4,157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.22 (4157 hom., cov: 32)
• Consequence: PITX2 ENST00000355080.9 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.836

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 4-110623439-T-A is Benign according to our data. Variant chr4-110623439-T-A is described in ClinVar as [Benign]. Clinvar id is 1247429.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITX2	NM_001204397.2	c.185-2070A>T		intron_variant			NP_001191326.1
PITX2	NM_001204398.1	c.185-2070A>T		intron_variant			NP_001191327.1
PITX2	NM_001204399.1	c.47-2070A>T		intron_variant			NP_001191328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000355080.9	c.47-2070A>T		intron_variant		1		ENSP00000347192	P1
PITX2	ENST00000354925.6	c.185-2070A>T		intron_variant		2		ENSP00000347004
PITX2	ENST00000394595.8	c.185-2070A>T		intron_variant		5		ENSP00000378095

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33049 AN: 152004 Hom.: 4141 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.218 AC: 33097 AN: 152122 Hom.: 4157 Cov.: 32 AF XY: 0.217 AC XY: 16135 AN XY: 74382

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.223

Alfa AF: 0.178 Hom.: 371

Bravo AF: 0.225

Asia WGS AF: 0.316 AC: 1096 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.7
DANN	Benign	0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17041968; hg19: chr4-111544595;