chr4-110618669-C-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000325.6(PITX2):​c.431G>C​(p.Arg144Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

PITX2
NM_000325.6 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.57

Publications

6 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: Labcorp Genetics (formerly Invitae), G2P
  • Axenfeld-Rieger syndrome type 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • ring dermoid of cornea
    Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
  • 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)

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000325.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-110618669-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197883.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 4-110618669-C-G is Pathogenic according to our data. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PITX2NM_000325.6 linkc.431G>C p.Arg144Pro missense_variant Exon 3 of 3 ENST00000644743.1 NP_000316.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PITX2ENST00000644743.1 linkc.431G>C p.Arg144Pro missense_variant Exon 3 of 3 NM_000325.6 ENSP00000495061.1 Q99697-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Axenfeld-Rieger syndrome type 1 Pathogenic:2
Dec 01, 1996
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Jun 23, 2022
Human Developmental Genetics Laboratory, Medical College of Wisconsin
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Inborn genetic diseases Pathogenic:1
Dec 13, 2018
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
.;.;D;D;.;D;D;D;.;D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
.;D;.;.;.;.;.;D;D;D;D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.5
.;.;H;H;.;H;H;H;.;.;.
PhyloP100
7.6
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-6.4
.;D;.;D;D;D;.;.;.;D;D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
.;D;.;D;D;D;.;.;.;D;D
Sift4G
Pathogenic
0.0010
.;D;.;D;D;D;D;D;D;D;.
Polyphen
1.0
D;D;D;D;D;D;D;D;D;.;.
Vest4
0.97, 0.97, 0.95, 0.96, 0.95
MutPred
0.90
.;.;Gain of methylation at K134 (P = 0.0707);Gain of methylation at K134 (P = 0.0707);.;Gain of methylation at K134 (P = 0.0707);Gain of methylation at K134 (P = 0.0707);Gain of methylation at K134 (P = 0.0707);.;Gain of methylation at K134 (P = 0.0707);.;
MVP
0.98
MPC
2.4
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.99
gMVP
1.0
Mutation Taster
=0/100
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893859; hg19: chr4-111539825; API