chr4-110623439-T-A

Variant names:

• chr4-110623439-T-A
• rs17041968
• ENST00000355080.9:c.47-2070A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_153426.3(PITX2):​c.185-2070A>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 NM_153426.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.836
• Publications: 1 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 -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 VariationId 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.

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.185-2070A>T		intron	N/A	NP_001191326.1	Q99697-1
	PITX2	NM_001204398.1		c.185-2070A>T		intron	N/A	NP_001191327.1	Q99697-1
	PITX2	NM_153426.3		c.185-2070A>T		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.47-2070A>T		intron	N/A	ENSP00000347192.5	Q99697-3
	PITX2	ENST00000354925.6	TSL:2	c.185-2070A>T		intron	N/A	ENSP00000347004.2	Q99697-1
	PITX2	ENST00000394595.8	TSL:5	c.185-2070A>T		intron	N/A	ENSP00000378095.4	Q99697-1

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

African (AFR) AF: 0.348 AC: 14426 AN: 41474

American (AMR) AF: 0.183 AC: 2791 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 589 AN: 3466

East Asian (EAS) AF: 0.258 AC: 1334 AN: 5162

South Asian (SAS) AF: 0.246 AC: 1187 AN: 4822

European-Finnish (FIN) AF: 0.148 AC: 1571 AN: 10594

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10559 AN: 67998

Other (OTH) AF: 0.223 AC: 471 AN: 2112

Alfa AF: 0.178 Hom.: 371

Bravo AF: 0.225

Asia WGS AF: 0.316 AC: 1096 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.70
CADD	Benign	8.7
DANN	Benign	0.68
PhyloP100		0.84
PromoterAI		0.065	Neutral
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: rs17041968; hg19: chr4-111544595;