rs662702

Variant names:

• chr11-31787522-C-T
• rs662702
• NM_019040.5:c.*3998C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019040.5(ELP4):​c.*3998C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 232,834 control chromosomes in the GnomAD database, including 2,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2395 hom., cov: 33)
  • Exomes 𝑓: 0.098 (511 hom.)
• Consequence: ELP4 NM_019040.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.687
• Publications: 33 publications found

Genes affected

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]

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]

PAX6 Gene-Disease associations (from GenCC):

• aniridia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• PAX6-related ocular dysgenesis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Peters anomaly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant keratitis

  Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• foveal hypoplasia-presenile cataract syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated aniridia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated optic nerve hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-31787522-C-T is Benign according to our data. Variant chr11-31787522-C-T is described in ClinVar as Benign. ClinVar VariationId is 304328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019040.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP4	NM_019040.5	MANE Select	c.*3998C>T		3_prime_UTR	Exon 10 of 10	NP_061913.3
	ELP4	NM_001288726.2		c.*4093C>T		3_prime_UTR	Exon 12 of 12	NP_001275655.1	G5E9D4
	ELP4	NM_001288725.2		c.*3984C>T		3_prime_UTR	Exon 11 of 11	NP_001275654.1	Q96EB1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP4	ENST00000640961.2	TSL:1 MANE Select	c.*3998C>T		3_prime_UTR	Exon 10 of 10	ENSP00000492152.1	Q96EB1-1
	PAX6	ENST00000419022.6	TSL:1	c.*2412G>A		3_prime_UTR	Exon 14 of 14	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.*2412G>A		3_prime_UTR	Exon 14 of 14	ENSP00000492315.2	P26367-2

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22126 AN: 152082 Hom.: 2383 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0824

Gnomad FIN AF: 0.0860

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0630

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.0976 AC: 7870 AN: 80634 Hom.: 511 Cov.: 0 AF XY: 0.0948 AC XY: 3516 AN XY: 37082

African (AFR) AF: 0.289 AC: 1117 AN: 3868

American (AMR) AF: 0.186 AC: 460 AN: 2478

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 559 AN: 5102

East Asian (EAS) AF: 0.125 AC: 1418 AN: 11372

South Asian (SAS) AF: 0.0755 AC: 53 AN: 702

European-Finnish (FIN) AF: 0.117 AC: 7 AN: 60

Middle Eastern (MID) AF: 0.177 AC: 87 AN: 492

European-Non Finnish (NFE) AF: 0.0684 AC: 3407 AN: 49822

Other (OTH) AF: 0.113 AC: 762 AN: 6738

GnomAD4 genome AF: 0.146 AC: 22168 AN: 152200 Hom.: 2395 Cov.: 33 AF XY: 0.146 AC XY: 10869 AN XY: 74420

African (AFR) AF: 0.296 AC: 12296 AN: 41494

American (AMR) AF: 0.165 AC: 2515 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 405 AN: 3468

East Asian (EAS) AF: 0.191 AC: 988 AN: 5180

South Asian (SAS) AF: 0.0812 AC: 392 AN: 4826

European-Finnish (FIN) AF: 0.0860 AC: 913 AN: 10612

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0630 AC: 4282 AN: 68014

Other (OTH) AF: 0.138 AC: 291 AN: 2112

Alfa AF: 0.0908 Hom.: 4191

Bravo AF: 0.162

Asia WGS AF: 0.167 AC: 580 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	11p partial monosomy syndrome (1)
-	-	1	Aniridia 1 (1)
-	-	1	Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis (1)
-	-	1	Anophthalmia-microphthalmia syndrome (1)
-	-	1	Autosomal dominant keratitis (1)
-	-	1	carboxymethyl-dextran-A2-gadolinium-DOTA (1)
-	-	1	Congenital aniridia (1)
-	-	1	Foveal hypoplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.67
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs662702; hg19: chr11-31809070;