rs667773

Positions:

chr11-31793814-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001368894.2(PAX6):c.808-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0583 in 1,613,838 control chromosomes in the GnomAD database, including 3,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.062 ( 401 hom., cov: 32)

Exomes 𝑓: 0.058 ( 3446 hom. )

Consequence

PAX6
NM_001368894.2 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001295

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: -0.149

Variant links:

Genes affected

PAX6 (HGNC:8620): (paired box 6) This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter's anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain. [provided by RefSeq, Mar 2019]

PAX6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 11-31793814-G-A is Benign according to our data. Variant chr11-31793814-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258168.We mark this variant Likely_benign, oryginal submissions are: {Benign=11, Uncertain_significance=1}. Variant chr11-31793814-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2 linkuse as main transcript	c.808-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2 linkuse as main transcript	c.808-12C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001368894.2	ENSP00000492024		P26367-2

Frequencies

GnomAD3 genomes

AF:

0.0617

AC:

9378

AN:

152074

Hom.:

401

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0418

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.0718

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.0689

Gnomad FIN

AF:

0.0499

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.0492

Gnomad OTH

AF:

0.0718

GnomAD3 exomes

AF:

0.0851

AC:

21382

AN:

251158

Hom.:

1523

AF XY:

0.0795

AC XY:

10792

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.0386

Gnomad AMR exome

AF:

0.201

Gnomad ASJ exome

AF:

0.0813

Gnomad EAS exome

AF:

0.198

Gnomad SAS exome

AF:

0.0685

Gnomad FIN exome

AF:

0.0496

Gnomad NFE exome

AF:

0.0501

Gnomad OTH exome

AF:

0.0822

GnomAD4 exome

AF:

0.0579

AC:

84652

AN:

1461646

Hom.:

3446

Cov.:

AF XY:

0.0576

AC XY:

41876

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0436

Gnomad4 AMR exome

AF:

0.193

Gnomad4 ASJ exome

AF:

0.0745

Gnomad4 EAS exome

AF:

0.148

Gnomad4 SAS exome

AF:

0.0697

Gnomad4 FIN exome

AF:

0.0520

Gnomad4 NFE exome

AF:

0.0476

Gnomad4 OTH exome

AF:

0.0709

GnomAD4 genome

AF:

0.0616

AC:

9373

AN:

152192

Hom.:

401

Cov.:

AF XY:

0.0639

AC XY:

4756

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0418

Gnomad4 AMR

AF:

0.130

Gnomad4 ASJ

AF:

0.0718

Gnomad4 EAS

AF:

0.193

Gnomad4 SAS

AF:

0.0681

Gnomad4 FIN

AF:

0.0499

Gnomad4 NFE

AF:

0.0492

Gnomad4 OTH

AF:

0.0710

Alfa

AF:

0.0558

Hom.:

Bravo

AF:

0.0704

Asia WGS

AF:

0.139

AC:

481

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Abnormality of refraction

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Mutations in PAX6 can predispose to neonatal diabetes along with extra pancreatic manifestation of optic abnormalities. However, no sufficient evidence was found for the role of rs667773 variant in Diabetes Mellitus yet. -

carboxymethyl-dextran-A2-gadolinium-DOTA

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Aniridia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Foveal hypoplasia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

11p partial monosomy syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Autosomal dominant keratitis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 19390808, 18776953, 12868034, 9727514, 27884173) -

Aniridia, Cerebellar Ataxia, And Intellectual Disability

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Anophthalmia-microphthalmia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.7

DANN

Benign

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000013

dbscSNV1_RF

Benign

0.0

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

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