rs35946364

Variant names:

• chr4-110618482-A-C
• rs35946364
• NM_000325.6:c.618T>G

Your query was ambiguous. Multiple possible variants found:

• chr4-110618482-A-C
• chr4-110618482-A-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BS1 BS2

The NM_000325.6(PITX2):​c.618T>G​(p.Ser206Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,886 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (22 hom.)
• Consequence: PITX2 NM_000325.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.535
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.276).
• BP6: Variant 4-110618482-A-C is Benign according to our data. Variant chr4-110618482-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.535 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1632/152168) while in subpopulation AFR AF = 0.0371 (1541/41486). AF 95% confidence interval is 0.0356. There are 35 homozygotes in GnomAd4. There are 796 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1632 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX2	NM_000325.6	MANE Select	c.618T>G	p.Ser206Ser	synonymous	Exon 3 of 3	NP_000316.2
	PITX2	NM_001204397.2		c.597T>G	p.Ser199Ser	synonymous	Exon 6 of 6	NP_001191326.1	Q99697-1
	PITX2	NM_001204398.1		c.597T>G	p.Ser199Ser	synonymous	Exon 5 of 5	NP_001191327.1	Q99697-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX2	ENST00000644743.1	MANE Select	c.618T>G	p.Ser206Ser	synonymous	Exon 3 of 3	ENSP00000495061.1	Q99697-2
	PITX2	ENST00000355080.9	TSL:1	c.459T>G	p.Ser153Ser	synonymous	Exon 4 of 4	ENSP00000347192.5	Q99697-3
	PITX2	ENST00000613094.5	TSL:5	c.391T>G	p.Tyr131Asp	missense	Exon 4 of 4	ENSP00000484763.2	A0A8J9G9V2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1633 AN: 152050 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00296 AC: 744 AN: 251454 AF XY: 0.00212

Gnomad AFR exome AF: 0.0388

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00119 AC: 1735 AN: 1461718 Hom.: 22 Cov.: 32 AF XY: 0.00102 AC XY: 742 AN XY: 727160

African (AFR) AF: 0.0364 AC: 1220 AN: 33476

American (AMR) AF: 0.00197 AC: 88 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1111854

Other (OTH) AF: 0.00265 AC: 160 AN: 60392

GnomAD4 genome AF: 0.0107 AC: 1632 AN: 152168 Hom.: 35 Cov.: 33 AF XY: 0.0107 AC XY: 796 AN XY: 74390

African (AFR) AF: 0.0371 AC: 1541 AN: 41486

American (AMR) AF: 0.00340 AC: 52 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00658 Hom.: 16

Bravo AF: 0.0124

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Anterior segment dysgenesis 1 (1)
-	-	1	Anterior segment dysgenesis 4;C3714873:Axenfeld-Rieger syndrome type 1 (1)
-	-	1	Axenfeld-Rieger syndrome type 1 (1)
-	-	1	Cataract (1)
-	-	1	Hypoplasia of the iris (1)
-	-	1	Irido-corneo-trabecular dysgenesis (1)
-	-	1	not specified (1)
-	-	1	PITX2-Related Eye Abnormalities (1)
-	-	1	Ring dermoid of cornea (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.6
DANN	Benign	0.80
PhyloP100		-0.54
Mutation Taster		=89/11	polymorphism

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: rs35946364; hg19: chr4-111539638; COSMIC: COSV100146275;