11-31509877-G-T

Position:

• chr11-31509877-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_019040.5(ELP4):​c.93G>T​(p.Arg31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (1 hom.)
• Consequence: ELP4 NM_019040.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.68

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28922504).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP4	NM_019040.5	c.93G>T	p.Arg31Ser	missense_variant	1/10	ENST00000640961.2	NP_061913.3
ELP4	NM_001288726.2	c.93G>T	p.Arg31Ser	missense_variant	1/12		NP_001275655.1
ELP4	NM_001288725.2	c.93G>T	p.Arg31Ser	missense_variant	1/11		NP_001275654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP4	ENST00000640961.2	c.93G>T	p.Arg31Ser	missense_variant	1/10	1	NM_019040.5	ENSP00000492152	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249428 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461840 Hom.: 1 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.00000826 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

May 05, 2023

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. 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. This variant has not been reported in the literature in individuals affected with ELP4-related conditions. This variant is present in population databases (rs373816333, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 31 of the ELP4 protein (p.Arg31Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.0	M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.82	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	.;.;N;.;N;.;.;.;.;.;.;.;N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	.;.;D;.;D;.;.;.;.;.;.;.;D
Sift4G	Uncertain	0.0070	.;.;D;.;D;.;.;.;.;.;.;.;D
Polyphen		0.98	D;.;.;.;.;.;.;.;.;.;.;.;D
Vest4		0.54, 0.64, 0.66
MutPred		0.50		Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);Gain of glycosylation at R31 (P = 0.0136);
MVP		0.61
MPC		0.33
ClinPred		0.83	D
GERP RS		3.7
Varity_R		0.48
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373816333; hg19: chr11-31531424;