11-31509801-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_019040.5(ELP4):c.17C>T(p.Thr6Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ELP4 NM_019040.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:2
• Conservation: PhyloP100: -0.248

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07606763).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP4	NM_019040.5	c.17C>T	p.Thr6Ile	missense_variant	1/10	ENST00000640961.2
ELP4	NM_001288726.2	c.17C>T	p.Thr6Ile	missense_variant	1/12
ELP4	NM_001288725.2	c.17C>T	p.Thr6Ile	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP4	ENST00000640961.2	c.17C>T	p.Thr6Ile	missense_variant	1/10	1	NM_019040.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249284 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135278

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: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727190

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: 0.0000288

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2023

The c.17C>T (p.T6I) alteration is located in exon 1 (coding exon 1) of the ELP4 gene. This alteration results from a C to T substitution at nucleotide position 17, causing the threonine (T) at amino acid position 6 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.014	T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.076	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L;.;L;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
Polyphen		0.0020	B;.;.;.;.;.;.;.;.;.;.;.;B
Vest4		0.37, 0.39, 0.37
MutPred		0.30		Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);Loss of glycosylation at T6 (P = 0.0101);
MVP		0.33
MPC		0.12
ClinPred		0.13	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.058
gMVP		0.33

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: rs760224399; hg19: chr11-31531348;