NM_001368894.2:c.1310A>G

Variant names:

• chr11-31789935-T-C
• rs121907922
• NM_001368894.2:c.1310A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001368894.2(PAX6):​c.1310A>G​(p.Ter437Ter) variant causes a stop retained change. The variant allele was found at a frequency of 0.000000772 in 1,295,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000075 (0 hom., cov: 27)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX6 NM_001368894.2 stop_retained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85
• Publications: 21 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.1310A>G	p.Ter437Ter	stop_retained_variant	Exon 14 of 14	ENST00000640368.2	NP_001355823.1
ELP4	NM_019040.5	c.*6411T>C		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.1310A>G	p.Ter437Ter	stop_retained_variant	Exon 14 of 14	5	NM_001368894.2	ENSP00000492024.1
ELP4	ENST00000640961.2	c.*6411T>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_019040.5	ENSP00000492152.1

Frequencies

GnomAD3 genomes AF: 0.00000745 AC: 1 AN: 134228 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000165

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1295916 Hom.: 0 Cov.: 30 AF XY: 0.00000154 AC XY: 1 AN XY: 648968

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29606

American (AMR) AF: 0.00 AC: 0 AN: 39718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24218

East Asian (EAS) AF: 0.00 AC: 0 AN: 38306

South Asian (SAS) AF: 0.00 AC: 0 AN: 76502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 976304

Other (OTH) AF: 0.00 AC: 0 AN: 54534

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000745 AC: 1 AN: 134228 Hom.: 0 Cov.: 27 AF XY: 0.0000154 AC XY: 1 AN XY: 65126

African (AFR) AF: 0.00 AC: 0 AN: 37320

American (AMR) AF: 0.00 AC: 0 AN: 13324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3138

East Asian (EAS) AF: 0.00 AC: 0 AN: 4968

South Asian (SAS) AF: 0.00 AC: 0 AN: 4246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0000165 AC: 1 AN: 60630

Other (OTH) AF: 0.00 AC: 0 AN: 1828

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.32	T;T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.58	D
PhyloP100		3.8
GERP RS		5.0
Mutation Taster		=99/1	polymorphism

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: rs121907922; hg19: chr11-31811483;