rs750848278

Variant names:

• chr11-31789936-A-G
• rs750848278
• NM_001368894.2:c.1309T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-31789936-A-G
• chr11-31789936-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM4 PP5_Very_Strong

The NM_001368894.2(PAX6):​c.1309T>C​(p.Ter437Glnext*?) variant causes a stop lost change. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX6 NM_001368894.2 stop_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.95
• Publications: 1 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]

ELP4 (HGNC:1171): (elongator acetyltransferase complex subunit 4) This gene encodes a component of the six subunit elongator complex, a histone acetyltransferase complex that associates directly with RNA polymerase II during transcriptional elongation. The human gene can partially complement sensitivity phenotypes of yeast ELP4 deletion mutants. This gene has also been associated with Rolandic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ELP4 Gene-Disease associations (from GenCC):

• aniridia 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp
• aniridia 1

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM4: Stoplost variant in NM_001368894.2 Downstream stopcodon found after 33 codons.
• PP5: Variant 11-31789936-A-G is Pathogenic according to our data. Variant chr11-31789936-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 800482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.1309T>C	p.Ter437Glnext*?	stop_lost	Exon 14 of 14	ENST00000640368.2	NP_001355823.1
ELP4	NM_019040.5	c.*6412A>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000640961.2	NP_061913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.1309T>C	p.Ter437Glnext*?	stop_lost	Exon 14 of 14	5	NM_001368894.2	ENSP00000492024.1
ELP4	ENST00000640961.2	c.*6412A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_019040.5	ENSP00000492152.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 868722 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 435140

African (AFR) AF: 0.00 AC: 0 AN: 17368

American (AMR) AF: 0.00 AC: 0 AN: 20004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16068

East Asian (EAS) AF: 0.00 AC: 0 AN: 27332

South Asian (SAS) AF: 0.00 AC: 0 AN: 39162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 673248

Other (OTH) AF: 0.00 AC: 0 AN: 36676

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 10, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Normal stop codon changed to a Gln codon, leading to the addition of 14 amino acids at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32360764) -

May 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aniridia 1 Pathogenic:1

Aug 15, 2019

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	13
DANN	Benign	0.72
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.0
Vest4		0.50
GERP RS		6.2
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs750848278; hg19: chr11-31811484;