Genetic Variant PITX2:c.*471G>A (chr4-110617654-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000325.6(PITX2):c.*471G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0103 in 183,298 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 32 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 0 hom. )

Consequence

PITX2
NM_000325.6 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.93

Publications

1 publications found

Variant links:

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)

PITX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 4-110617654-C-T is Benign according to our data. Variant chr4-110617654-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 347291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1871/152270) while in subpopulation AFR AF = 0.0428 (1777/41550). AF 95% confidence interval is 0.0411. There are 32 homozygotes in GnomAd4. There are 910 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1871 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000325.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PITX2	NM_000325.6	MANE Select	c.*471G>A	3_prime_UTR	Exon 3 of 3	NP_000316.2
PITX2	NM_001204397.2		c.*471G>A	3_prime_UTR	Exon 6 of 6	NP_001191326.1	Q99697-1
PITX2	NM_001204398.1		c.*471G>A	3_prime_UTR	Exon 5 of 5	NP_001191327.1	Q99697-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PITX2	ENST00000644743.1	MANE Select	c.*471G>A	3_prime_UTR	Exon 3 of 3	ENSP00000495061.1	Q99697-2
PITX2	ENST00000355080.9	TSL:1	c.*471G>A	3_prime_UTR	Exon 4 of 4	ENSP00000347192.5	Q99697-3
PITX2	ENST00000354925.6	TSL:2	c.*471G>A	3_prime_UTR	Exon 7 of 7	ENSP00000347004.2	Q99697-1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1862

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0427

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00956

GnomAD4 exome

AF:

0.000709

AC:

AN:

31028

Hom.:

Cov.:

AF XY:

0.000691

AC XY:

AN XY:

15920

show subpopulations

African (AFR)

AF:

0.0262

AC:

AN:

382

American (AMR)

AF:

0.00257

AC:

AN:

3116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

596

East Asian (EAS)

AF:

0.00

AC:

AN:

1506

South Asian (SAS)

AF:

0.00

AC:

AN:

3896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1716

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

18126

Other (OTH)

AF:

0.00187

AC:

AN:

1606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.557

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0123

AC:

1871

AN:

152270

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

910

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0428

AC:

1777

AN:

41550

American (AMR)

AF:

0.00412

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68016

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

180

270

360

450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00878

Hom.:

Bravo

AF:

0.0138

Asia WGS

AF:

0.00289

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Anterior segment dysgenesis 4 (1)

Axenfeld-Rieger syndrome type 1 (1)

Cataract (1)

Hypoplasia of the iris (1)

Irido-corneo-trabecular dysgenesis (1)

not provided (1)

PITX2-Related Eye Abnormalities (1)

Ring dermoid of cornea (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

4.9

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over