rs1540320

Variant names:

• chr11-31815895-C-T
• rs1540320
• ENST00000638914.3:c.-317+1914G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000638914.3(PAX6):​c.-317+1914G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 152,166 control chromosomes in the GnomAD database, including 3,099 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 0.20 (3099 hom., cov: 34)
• Consequence: PAX6 ENST00000638914.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 6 publications found

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]

ENSG00000285283 (HGNC:):

PAUPAR (HGNC:49670): (PAX6 upstream antisense RNA) This gene is thought to produce a functional long non-coding RNA. Knockdown of this transcript results in genome-wide changes in gene expression, particularly of cell cyle genes, indicating a role in regulating differentiation. This transcript may bind to the promoter region of target genes and may also interact with the transcription factor Pax6 (paired box 6). [provided by RefSeq, Feb 2015]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368919.2	c.-317+1914G>A		intron_variant	Intron 1 of 13		NP_001355848.1
PAX6	NM_001258462.3	c.-317+1914G>A		intron_variant	Intron 1 of 13		NP_001245391.1
PAX6	NM_001127612.3	c.-317+1914G>A		intron_variant	Intron 1 of 12		NP_001121084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000638914.3	c.-317+1914G>A		intron_variant	Intron 1 of 13	1		ENSP00000492315.2
PAX6	ENST00000241001.13	c.-317+1914G>A		intron_variant	Intron 1 of 12	1		ENSP00000241001.8
PAX6	ENST00000379129.7	c.-129+1914G>A		intron_variant	Intron 1 of 12	5		ENSP00000368424.2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29975 AN: 152048 Hom.: 3097 Cov.: 34

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.170

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.197 AC: 30007 AN: 152166 Hom.: 3099 Cov.: 34 AF XY: 0.197 AC XY: 14674 AN XY: 74392

African (AFR) AF: 0.231 AC: 9590 AN: 41512

American (AMR) AF: 0.202 AC: 3087 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3468

East Asian (EAS) AF: 0.295 AC: 1528 AN: 5176

South Asian (SAS) AF: 0.184 AC: 888 AN: 4830

European-Finnish (FIN) AF: 0.198 AC: 2095 AN: 10564

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11896 AN: 67992

Other (OTH) AF: 0.167 AC: 354 AN: 2114

Alfa AF: 0.188 Hom.: 1335

Bravo AF: 0.199

Asia WGS AF: 0.220 AC: 762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.9
DANN	Benign	0.93
PhyloP100		-1.3
PromoterAI		-0.031	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1540320; hg19: chr11-31837443;