rs2278782

Variant names:

• chr4-110620998-G-A
• rs2278782
• NM_000325.6:c.411+166C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000325.6(PITX2):​c.411+166C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 713,554 control chromosomes in the GnomAD database, including 8,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1660 hom., cov: 34)
  • Exomes 𝑓: 0.16 (7316 hom.)
• Consequence: PITX2 NM_000325.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.736
• Publications: 6 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: 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.764495).
• BP6: Variant 4-110620998-G-A is Benign according to our data. Variant chr4-110620998-G-A is described in ClinVar as Benign. ClinVar VariationId is 1238490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX2	NM_000325.6	c.411+166C>T		intron_variant	Intron 2 of 2	ENST00000644743.1	NP_000316.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000644743.1	c.411+166C>T		intron_variant	Intron 2 of 2		NM_000325.6	ENSP00000495061.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22409 AN: 152210 Hom.: 1661 Cov.: 34

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.155 AC: 20896 AN: 135170 AF XY: 0.158

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.157 AC: 88160 AN: 561226 Hom.: 7316 Cov.: 5 AF XY: 0.159 AC XY: 48208 AN XY: 303080

African (AFR) AF: 0.143 AC: 2291 AN: 16004

American (AMR) AF: 0.130 AC: 4523 AN: 34690

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3131 AN: 20078

East Asian (EAS) AF: 0.190 AC: 6115 AN: 32126

South Asian (SAS) AF: 0.185 AC: 11670 AN: 62940

European-Finnish (FIN) AF: 0.120 AC: 4085 AN: 33912

Middle Eastern (MID) AF: 0.187 AC: 767 AN: 4108

European-Non Finnish (NFE) AF: 0.155 AC: 50635 AN: 326464

Other (OTH) AF: 0.160 AC: 4943 AN: 30904

GnomAD4 genome AF: 0.147 AC: 22411 AN: 152328 Hom.: 1660 Cov.: 34 AF XY: 0.147 AC XY: 10927 AN XY: 74486

African (AFR) AF: 0.138 AC: 5755 AN: 41582

American (AMR) AF: 0.148 AC: 2265 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 536 AN: 3472

East Asian (EAS) AF: 0.159 AC: 820 AN: 5172

South Asian (SAS) AF: 0.187 AC: 903 AN: 4834

European-Finnish (FIN) AF: 0.121 AC: 1290 AN: 10618

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10361 AN: 68018

Other (OTH) AF: 0.152 AC: 322 AN: 2116

Alfa AF: 0.153 Hom.: 1256

Bravo AF: 0.147

TwinsUK AF: 0.154 AC: 571

ALSPAC AF: 0.143 AC: 553

ExAC AF: 0.0804 AC: 3335

Asia WGS AF: 0.202 AC: 701 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.89
FATHMM_MKL	Benign	0.64	D
PhyloP100		0.74
Vest4		0.23
GERP RS		2.7
Mutation Taster		=179/21	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2278782; hg19: chr4-111542154; COSMIC: COSV60740084; COSMIC: COSV60740084;