11-31813870-A-G

Variant names:

• chr11-31813870-A-G
• rs7942007
• ENST00000638914.3:c.-316-2855T>C

Variant summary

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

The ENST00000638914.3(PAX6):​c.-316-2855T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 151,800 control chromosomes in the GnomAD database, including 2,999 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 (2999 hom., cov: 31)
• Consequence: PAX6 ENST00000638914.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.96
• Publications: 14 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000638914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	NM_001368919.2		c.-316-2855T>C		intron	N/A	NP_001355848.1
	PAX6	NM_001258462.3		c.-316-2855T>C		intron	N/A	NP_001245391.1
	PAX6	NM_001127612.3		c.-316-2855T>C		intron	N/A	NP_001121084.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	ENST00000638914.3	TSL:1	c.-316-2855T>C		intron	N/A	ENSP00000492315.2
	PAX6	ENST00000241001.13	TSL:1	c.-316-2855T>C		intron	N/A	ENSP00000241001.8
	PAX6	ENST00000379129.7	TSL:5	c.-129+3939T>C		intron	N/A	ENSP00000368424.2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29633 AN: 151680 Hom.: 2993 Cov.: 31

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.172

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

GnomAD4 genome AF: 0.195 AC: 29672 AN: 151800 Hom.: 2999 Cov.: 31 AF XY: 0.198 AC XY: 14679 AN XY: 74186

African (AFR) AF: 0.218 AC: 9006 AN: 41388

American (AMR) AF: 0.206 AC: 3142 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3470

East Asian (EAS) AF: 0.303 AC: 1556 AN: 5134

South Asian (SAS) AF: 0.190 AC: 913 AN: 4798

European-Finnish (FIN) AF: 0.218 AC: 2302 AN: 10544

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

European-Non Finnish (NFE) AF: 0.175 AC: 11853 AN: 67894

Other (OTH) AF: 0.170 AC: 357 AN: 2102

Alfa AF: 0.176 Hom.: 4115

Bravo AF: 0.197

Asia WGS AF: 0.223 AC: 773 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.69
DANN	Benign	0.39
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs7942007; hg19: chr11-31835418;