NM_019040.5:c.127G>T

Variant names:

• chr11-31509911-G-T
• rs201513124
• NM_019040.5:c.127G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_019040.5(ELP4):​c.127G>T​(p.Gly43Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ELP4 NM_019040.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15364602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP4	NM_019040.5	c.127G>T	p.Gly43Cys	missense_variant	Exon 1 of 10	ENST00000640961.2	NP_061913.3
ELP4	NM_001288726.2	c.127G>T	p.Gly43Cys	missense_variant	Exon 1 of 12		NP_001275655.1
ELP4	NM_001288725.2	c.127G>T	p.Gly43Cys	missense_variant	Exon 1 of 11		NP_001275654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP4	ENST00000640961.2	c.127G>T	p.Gly43Cys	missense_variant	Exon 1 of 10	1	NM_019040.5	ENSP00000492152.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152200 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249120 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461730 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 43 of the ELP4 protein (p.Gly43Cys). This variant has not been reported in the literature in individuals affected with ELP4-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;L;.;.;.;.;.;.;.;.;.;.
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	.;.;N;.;N;.;.;.;.;.;.;.;N
REVEL	Benign	0.031
Sift	Benign	0.12	.;.;T;.;T;.;.;.;.;.;.;.;D
Sift4G	Benign	0.19	.;.;T;.;T;.;.;.;.;.;.;.;T
Polyphen		0.020	B;.;.;.;.;.;.;.;.;.;.;.;P
Vest4		0.19, 0.20, 0.22
MutPred		0.42		Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);Loss of catalytic residue at G43 (P = 0.0186);
MVP		0.66
MPC		0.059
ClinPred		0.36	T
GERP RS		3.6
PromoterAI		-0.11	Neutral
Varity_R		0.12
gMVP		0.46
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs201513124; hg19: chr11-31531458;