rs608293

Variant names:

• chr11-31786732-C-T
• rs608293
• NM_019040.5:c.*3208C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-31786732-C-T
• chr11-31786732-C-G

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.*3208C>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 0.86 in 224,348 control chromosomes in the GnomAD database, including 83,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58661 hom., cov: 33)
  • Exomes 𝑓: 0.83 (24946 hom.)
• Consequence: ELP4 NM_019040.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.697
• Publications: 10 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=-0.87).
• BP6: Variant 11-31786732-C-T is Benign according to our data. Variant chr11-31786732-C-T is described in ClinVar as Benign. ClinVar VariationId is 304310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.957 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.*3208C>T		3_prime_UTR	Exon 10 of 10	NP_061913.3
	ELP4	NM_001288726.2		c.*3303C>T		3_prime_UTR	Exon 12 of 12	NP_001275655.1	G5E9D4
	ELP4	NM_001288725.2		c.*3194C>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.*3208C>T		3_prime_UTR	Exon 10 of 10	ENSP00000492152.1	Q96EB1-1
	PAX6	ENST00000419022.6	TSL:1	c.*3202G>A		3_prime_UTR	Exon 14 of 14	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.*3202G>A		3_prime_UTR	Exon 14 of 14	ENSP00000492315.2	P26367-2

Frequencies

GnomAD3 genomes AF: 0.875 AC: 133177 AN: 152140 Hom.: 58604 Cov.: 33

Gnomad AFR AF: 0.965

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.884

GnomAD4 exome AF: 0.828 AC: 59675 AN: 72090 Hom.: 24946 Cov.: 0 AF XY: 0.831 AC XY: 27606 AN XY: 33236

African (AFR) AF: 0.959 AC: 3256 AN: 3396

American (AMR) AF: 0.802 AC: 1799 AN: 2244

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 3830 AN: 4558

East Asian (EAS) AF: 0.649 AC: 6682 AN: 10292

South Asian (SAS) AF: 0.844 AC: 530 AN: 628

European-Finnish (FIN) AF: 0.840 AC: 42 AN: 50

Middle Eastern (MID) AF: 0.916 AC: 414 AN: 452

European-Non Finnish (NFE) AF: 0.855 AC: 38017 AN: 44482

Other (OTH) AF: 0.853 AC: 5105 AN: 5988

GnomAD4 genome AF: 0.875 AC: 133294 AN: 152258 Hom.: 58661 Cov.: 33 AF XY: 0.872 AC XY: 64869 AN XY: 74420

African (AFR) AF: 0.965 AC: 40122 AN: 41574

American (AMR) AF: 0.823 AC: 12578 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 2962 AN: 3470

East Asian (EAS) AF: 0.723 AC: 3741 AN: 5176

South Asian (SAS) AF: 0.828 AC: 3994 AN: 4822

European-Finnish (FIN) AF: 0.821 AC: 8694 AN: 10584

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.857 AC: 58275 AN: 68024

Other (OTH) AF: 0.885 AC: 1873 AN: 2116

Alfa AF: 0.863 Hom.: 19750

Bravo AF: 0.878

Asia WGS AF: 0.805 AC: 2801 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, 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	-0.87
CADD	Benign	0.20
DANN	Benign	0.69
PhyloP100		-0.70
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: rs608293; hg19: chr11-31808280;