NM_019040.5:c.*5226T>A

Variant names:

• chr11-31788750-T-A
• rs1506
• NM_019040.5:c.*5226T>A

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.*5226T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 206,598 control chromosomes in the GnomAD database, including 55,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40255 hom., cov: 30)
  • Exomes 𝑓: 0.73 (14936 hom.)
• Consequence: ELP4 NM_019040.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.256
• Publications: 15 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: Genomics England PanelApp, G2P, 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: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• coloboma, ocular, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• diabetes mellitus

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

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

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 11-31788750-T-A is Benign according to our data. Variant chr11-31788750-T-A is described in ClinVar as Benign. ClinVar VariationId is 304341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.8 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.*5226T>A		3_prime_UTR	Exon 10 of 10	NP_061913.3
	ELP4	NM_001288726.2		c.*5321T>A		3_prime_UTR	Exon 12 of 12	NP_001275655.1
	ELP4	NM_001288725.2		c.*5212T>A		3_prime_UTR	Exon 11 of 11	NP_001275654.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP4	ENST00000640961.2	TSL:1 MANE Select	c.*5226T>A		3_prime_UTR	Exon 10 of 10	ENSP00000492152.1
	PAX6	ENST00000419022.6	TSL:1	c.*1184A>T		3_prime_UTR	Exon 14 of 14	ENSP00000404100.1
	PAX6	ENST00000638914.3	TSL:1	c.*1184A>T		3_prime_UTR	Exon 14 of 14	ENSP00000492315.2

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109455 AN: 151830 Hom.: 40238 Cov.: 30

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.871

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.740

GnomAD4 exome AF: 0.729 AC: 39835 AN: 54650 Hom.: 14936 Cov.: 0 AF XY: 0.736 AC XY: 18850 AN XY: 25620

African (AFR) AF: 0.597 AC: 1432 AN: 2400

American (AMR) AF: 0.588 AC: 956 AN: 1626

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 2669 AN: 3416

East Asian (EAS) AF: 0.505 AC: 4227 AN: 8364

South Asian (SAS) AF: 0.760 AC: 351 AN: 462

European-Finnish (FIN) AF: 0.757 AC: 515 AN: 680

Middle Eastern (MID) AF: 0.754 AC: 255 AN: 338

European-Non Finnish (NFE) AF: 0.795 AC: 26052 AN: 32784

Other (OTH) AF: 0.738 AC: 3378 AN: 4580

GnomAD4 genome AF: 0.721 AC: 109511 AN: 151948 Hom.: 40255 Cov.: 30 AF XY: 0.717 AC XY: 53285 AN XY: 74270

African (AFR) AF: 0.603 AC: 24948 AN: 41392

American (AMR) AF: 0.654 AC: 9985 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 2731 AN: 3472

East Asian (EAS) AF: 0.523 AC: 2700 AN: 5158

South Asian (SAS) AF: 0.757 AC: 3642 AN: 4810

European-Finnish (FIN) AF: 0.774 AC: 8167 AN: 10546

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.806 AC: 54769 AN: 67984

Other (OTH) AF: 0.743 AC: 1570 AN: 2114

Alfa AF: 0.764 Hom.: 5273

Bravo AF: 0.704

Asia WGS AF: 0.630 AC: 2193 AN: 3474

ClinVar

ClinVar submissions as Germline

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	-0.97
CADD	Benign	0.36
DANN	Benign	0.46
PhyloP100		0.26
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: rs1506; hg19: chr11-31810298;