ENST00000638914.3:c.-317+2730G>A

Variant names:

• chr11-31815079-C-T
• rs1806159
• ENST00000638914.3:c.-317+2730G>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+2730G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 150,562 control chromosomes in the GnomAD database, including 1,948 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 0.15 (1946 hom., cov: 30)
  • Exomes 𝑓: 0.13 (2 hom.)
• Consequence: PAX6 ENST00000638914.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 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.-317+2730G>A		intron	N/A	NP_001355848.1
	PAX6	NM_001258462.3		c.-317+2730G>A		intron	N/A	NP_001245391.1
	PAX6	NM_001127612.3		c.-317+2730G>A		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.-317+2730G>A		intron	N/A	ENSP00000492315.2
	PAX6	ENST00000241001.13	TSL:1	c.-317+2730G>A		intron	N/A	ENSP00000241001.8
	PAX6	ENST00000379129.7	TSL:5	c.-129+2730G>A		intron	N/A	ENSP00000368424.2

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22307 AN: 150340 Hom.: 1948 Cov.: 30

Gnomad AFR AF: 0.0663

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.116

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.125 AC: 13 AN: 104 Hom.: 2 AF XY: 0.131 AC XY: 11 AN XY: 84

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.167 AC: 1 AN: 6

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.111 AC: 8 AN: 72

Other (OTH) AF: 0.375 AC: 3 AN: 8

GnomAD4 genome AF: 0.148 AC: 22318 AN: 150458 Hom.: 1946 Cov.: 30 AF XY: 0.150 AC XY: 11014 AN XY: 73374

African (AFR) AF: 0.0664 AC: 2705 AN: 40758

American (AMR) AF: 0.186 AC: 2808 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 414 AN: 3458

East Asian (EAS) AF: 0.293 AC: 1470 AN: 5014

South Asian (SAS) AF: 0.180 AC: 850 AN: 4730

European-Finnish (FIN) AF: 0.193 AC: 2001 AN: 10350

Middle Eastern (MID) AF: 0.117 AC: 34 AN: 290

European-Non Finnish (NFE) AF: 0.172 AC: 11649 AN: 67724

Other (OTH) AF: 0.131 AC: 274 AN: 2088

Alfa AF: 0.0733 Hom.: 89

Bravo AF: 0.145

Asia WGS AF: 0.208 AC: 720 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.0
DANN	Benign	0.53
PhyloP100		-1.1
PromoterAI		-0.010	Neutral
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: rs1806159; hg19: chr11-31836627; COSMIC: COSV53793836; COSMIC: COSV53793836;