11-31603795-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_019040.5(ELP4):c.541G>A(p.Gly181Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,608,232 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ELP4 NM_019040.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP4	NM_019040.5	c.541G>A	p.Gly181Ser	missense_variant	5/10	ENST00000640961.2
ELP4	NM_001288726.2	c.541G>A	p.Gly181Ser	missense_variant	5/12
ELP4	NM_001288725.2	c.544G>A	p.Gly182Ser	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP4	ENST00000640961.2	c.541G>A	p.Gly181Ser	missense_variant	5/10	1	NM_019040.5	P3

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151582 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247056 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1456650 Hom.: 0 Cov.: 30 AF XY: 0.00000690 AC XY: 5 AN XY: 724672

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000761

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151582 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74002

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 26, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 181 of the ELP4 protein (p.Gly181Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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	Benign	0.19
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;D
Vest4		0.81, 0.90
MutPred		0.77		Gain of phosphorylation at G181 (P = 0.0313);Gain of phosphorylation at G181 (P = 0.0313);.;Gain of phosphorylation at G181 (P = 0.0313);.;Gain of phosphorylation at G181 (P = 0.0313);.;Gain of phosphorylation at G181 (P = 0.0313);.;Gain of phosphorylation at G181 (P = 0.0313);Gain of phosphorylation at G181 (P = 0.0313);Gain of phosphorylation at G181 (P = 0.0313);
MVP		0.72
MPC		0.25
ClinPred		0.92	D
GERP RS		6.1
Varity_R		0.85
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1278665622; hg19: chr11-31625342;