NM_019040.5:c.*2452C>T

Variant names:

• chr11-31785976-C-T
• rs3026401
• NM_019040.5:c.*2452C>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.*2452C>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 0.709 in 200,448 control chromosomes in the GnomAD database, including 51,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38699 hom., cov: 33)
  • Exomes 𝑓: 0.72 (12714 hom.)
• Consequence: ELP4 NM_019040.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.350
• Publications: 18 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=-0.8).
• BP6: Variant 11-31785976-C-T is Benign according to our data. Variant chr11-31785976-C-T is described in ClinVar as Benign. ClinVar VariationId is 304301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.787 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.*2452C>T		3_prime_UTR	Exon 10 of 10	NP_061913.3
	ELP4	NM_001288726.2		c.*2547C>T		3_prime_UTR	Exon 12 of 12	NP_001275655.1	G5E9D4
	ELP4	NM_001288725.2		c.*2438C>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.*2452C>T		3_prime_UTR	Exon 10 of 10	ENSP00000492152.1	Q96EB1-1
	PAX6	ENST00000419022.6	TSL:1	c.*3958G>A		3_prime_UTR	Exon 14 of 14	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.*3958G>A		3_prime_UTR	Exon 14 of 14	ENSP00000492315.2	P26367-2

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107369 AN: 151882 Hom.: 38680 Cov.: 33

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.739

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.793

Gnomad OTH AF: 0.724

GnomAD4 exome AF: 0.716 AC: 34688 AN: 48448 Hom.: 12714 Cov.: 0 AF XY: 0.724 AC XY: 16237 AN XY: 22414

African (AFR) AF: 0.593 AC: 1250 AN: 2108

American (AMR) AF: 0.614 AC: 845 AN: 1376

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2320 AN: 3138

East Asian (EAS) AF: 0.486 AC: 3776 AN: 7768

South Asian (SAS) AF: 0.752 AC: 316 AN: 420

European-Finnish (FIN) AF: 0.679 AC: 19 AN: 28

Middle Eastern (MID) AF: 0.723 AC: 217 AN: 300

European-Non Finnish (NFE) AF: 0.785 AC: 23019 AN: 29326

Other (OTH) AF: 0.734 AC: 2926 AN: 3984

GnomAD4 genome AF: 0.707 AC: 107429 AN: 152000 Hom.: 38699 Cov.: 33 AF XY: 0.703 AC XY: 52188 AN XY: 74288

African (AFR) AF: 0.597 AC: 24730 AN: 41434

American (AMR) AF: 0.647 AC: 9889 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2576 AN: 3470

East Asian (EAS) AF: 0.487 AC: 2516 AN: 5164

South Asian (SAS) AF: 0.740 AC: 3569 AN: 4822

European-Finnish (FIN) AF: 0.736 AC: 7778 AN: 10568

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.793 AC: 53866 AN: 67944

Other (OTH) AF: 0.727 AC: 1537 AN: 2114

Alfa AF: 0.760 Hom.: 136876

Bravo AF: 0.692

Asia WGS AF: 0.603 AC: 2099 AN: 3474

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, Cerebellar Ataxia, And Intellectual Disability (1)
-	-	1	Anophthalmia-microphthalmia syndrome (1)
-	-	1	Autosomal dominant keratitis (1)
-	-	1	carboxymethyl-dextran-A2-gadolinium-DOTA (1)
-	-	1	Foveal hypoplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.58
PhyloP100		0.35
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: rs3026401; hg19: chr11-31807524;