11-31594897-T-C

Variant names:

• chr11-31594897-T-C
• rs1024940919
• NM_019040.5:c.509T>C

Variant summary

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

The NM_019040.5(ELP4):​c.509T>C​(p.Met170Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000499 in 1,401,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: ELP4 NM_019040.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

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=0.3066706).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP4	NM_019040.5	c.509T>C	p.Met170Thr	missense_variant	Exon 4 of 10	ENST00000640961.2	NP_061913.3
ELP4	NM_001288726.2	c.509T>C	p.Met170Thr	missense_variant	Exon 4 of 12		NP_001275655.1
ELP4	NM_001288725.2	c.509T>C	p.Met170Thr	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.509T>C	p.Met170Thr	missense_variant	Exon 4 of 10	1	NM_019040.5	ENSP00000492152.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000511 AC: 1 AN: 195762 Hom.: 0 AF XY: 0.00000927 AC XY: 1 AN XY: 107890

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000499 AC: 7 AN: 1401588 Hom.: 0 Cov.: 30 AF XY: 0.00000431 AC XY: 3 AN XY: 695732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000641

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 170 of the ELP4 protein (p.Met170Thr). 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. 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 tolerated. 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	0.21
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.020	T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M;.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	.;.;N;.;N;.;.;.;.;.;.;N
REVEL	Benign	0.16
Sift	Benign	0.14	.;.;T;.;D;.;.;.;.;.;.;T
Sift4G	Benign	0.18	.;.;T;.;T;.;.;.;.;.;.;D
Polyphen		0.48	P;.;.;.;.;.;.;.;.;.;.;P
Vest4		0.41, 0.41, 0.44
MutPred		0.62		Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);Gain of methylation at K169 (P = 0.0284);
MVP		0.57
MPC		0.12
ClinPred		0.55	D
GERP RS		5.1
Varity_R		0.35
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1024940919; hg19: chr11-31616444;