rs3026389

Positions:

• chr11-31791981-C-G
• chr11-31791981-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001368894.2(PAX6):​c.1075-1121G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 152,196 control chromosomes in the GnomAD database, including 37,076 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.68 (37076 hom., cov: 34)
  • Failed GnomAD Quality Control
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.709

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX6	NM_001368894.2	c.1075-1121G>C		intron_variant		ENST00000640368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX6	ENST00000640368.2	c.1075-1121G>C		intron_variant		5	NM_001368894.2

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103571 AN: 152078 Hom.: 37063 Cov.: 34

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.871

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.710

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.681 AC: 103614 AN: 152196 Hom.: 37076 Cov.: 34 AF XY: 0.679 AC XY: 50499 AN XY: 74410

Gnomad4 AFR AF: 0.470

Gnomad4 AMR AF: 0.642

Gnomad4 ASJ AF: 0.786

Gnomad4 EAS AF: 0.485

Gnomad4 SAS AF: 0.751

Gnomad4 FIN AF: 0.771

Gnomad4 NFE AF: 0.805

Gnomad4 OTH AF: 0.713

Alfa AF: 0.742 Hom.: 5342

Bravo AF: 0.659

Asia WGS AF: 0.610 AC: 2124 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.30
DANN	Benign	0.32

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

LitVar

Other links and lift over

dbSNP: rs3026389; hg19: chr11-31813529;