11-31594882-A-C

Variant names:

• chr11-31594882-A-C
• rs1957646200
• NM_019040.5:c.494A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_019040.5(ELP4):​c.494A>C​(p.Gln165Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,407,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ELP4 NM_019040.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91
• Publications: 0 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]

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP4	NM_019040.5	c.494A>C	p.Gln165Pro	missense_variant	Exon 4 of 10	ENST00000640961.2	NP_061913.3
ELP4	NM_001288726.2	c.494A>C	p.Gln165Pro	missense_variant	Exon 4 of 12		NP_001275655.1
ELP4	NM_001288725.2	c.494A>C	p.Gln165Pro	missense_variant	Exon 4 of 11		NP_001275654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP4	ENST00000640961.2	c.494A>C	p.Gln165Pro	missense_variant	Exon 4 of 10	1	NM_019040.5	ENSP00000492152.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407920 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 698832

African (AFR) AF: 0.00 AC: 0 AN: 30128

American (AMR) AF: 0.0000317 AC: 1 AN: 31500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24848

East Asian (EAS) AF: 0.00 AC: 0 AN: 36836

South Asian (SAS) AF: 0.00 AC: 0 AN: 73798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093966

Other (OTH) AF: 0.00 AC: 0 AN: 58168

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.494A>C (p.Q165P) alteration is located in exon 4 (coding exon 4) of the ELP4 gene. This alteration results from a A to C substitution at nucleotide position 494, causing the glutamine (Q) at amino acid position 165 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Dec 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 165 of the ELP4 protein (p.Gln165Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ELP4-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.4	M;.;M;.;.;.;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.2	.;.;D;.;D;.;.;.;.;.;.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	.;.;D;.;D;.;.;.;.;.;.;D
Sift4G	Uncertain	0.0050	.;.;D;.;D;.;.;.;.;.;.;D
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;D
Vest4		0.76, 0.78, 0.80
MutPred		0.72		Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);
MVP		0.78
MPC		0.37
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.86
gMVP		0.80
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1957646200; hg19: chr11-31616429;