Variant 10-102230682-C-CGCG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3BS1_SupportingBS2

The NM_005029.4(PITX3):c.740_741insCGC(p.Ala249dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.000537 in 1,578,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00057 ( 0 hom. )

Consequence

PITX3
NM_005029.4 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.42

Variant links:

Genes affected

PITX3 (HGNC:9006): (paired like homeodomain 3) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family act as transcription factors. This protein is involved in lens formation during eye development. Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis and congenital cataracts. [provided by RefSeq, Jul 2008]

PITX3 links:

GBF1 (HGNC:):

GBF1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005029.4

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000243 (37/152214) while in subpopulation NFE AF= 0.000382 (26/67980). AF 95% confidence interval is 0.000267. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PITX3	NM_005029.4 linkuse as main transcript	c.740_741insCGC	p.Ala249dup	inframe_insertion	4/4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1 linkuse as main transcript	c.740_741insCGC	p.Ala249dup	inframe_insertion	3/3		XP_047281308.1
GBF1	NM_001391923.1 linkuse as main transcript	c.-230_-228dup		5_prime_UTR_variant	1/40		NP_001378852.1
GBF1	NM_001391924.1 linkuse as main transcript	c.-368_-366dup		5_prime_UTR_variant	1/41		NP_001378853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITX3	ENST00000370002.8 linkuse as main transcript	c.740_741insCGC	p.Ala249dup	inframe_insertion	4/4	1	NM_005029.4	ENSP00000359019	P1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000256

AC:

AN:

175826

Hom.:

AF XY:

0.000230

AC XY:

AN XY:

95526

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000275

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000407

Gnomad FIN exome

AF:

0.0000606

Gnomad NFE exome

AF:

0.000469

Gnomad OTH exome

AF:

0.000218

GnomAD4 exome

AF:

0.000568

AC:

810

AN:

1426408

Hom.:

Cov.:

AF XY:

0.000536

AC XY:

379

AN XY:

706706

show subpopulations

Gnomad4 AFR exome

AF:

0.000153

Gnomad4 AMR exome

AF:

0.000234

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000244

Gnomad4 FIN exome

AF:

0.0000600

Gnomad4 NFE exome

AF:

0.000708

Gnomad4 OTH exome

AF:

0.000271

GnomAD4 genome

AF:

0.000243

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This variant, c.738_740dup, results in the insertion of 1 amino acid(s) of the PITX3 protein (p.Ala250dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs775510715, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PITX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 665913). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over