11-31594824-G-A

Variant names:

• chr11-31594824-G-A
• rs144056743
• NM_019040.5:c.436G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019040.5(ELP4):​c.436G>A​(p.Val146Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V146L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ELP4 NM_019040.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.376
• Publications: 0 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
• ocular dysgenesis caused by defects in PAX6 regulation

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• aniridia 1

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061116368).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019040.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP4	NM_019040.5	MANE Select	c.436G>A	p.Val146Ile	missense	Exon 4 of 10	NP_061913.3
	ELP4	NM_001288726.2		c.436G>A	p.Val146Ile	missense	Exon 4 of 12	NP_001275655.1	G5E9D4
	ELP4	NM_001288725.2		c.436G>A	p.Val146Ile	missense	Exon 4 of 11	NP_001275654.1	Q96EB1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP4	ENST00000640961.2	TSL:1 MANE Select	c.436G>A	p.Val146Ile	missense	Exon 4 of 10	ENSP00000492152.1	Q96EB1-1
	ELP4	ENST00000395934.2	TSL:1	c.436G>A	p.Val146Ile	missense	Exon 4 of 12	ENSP00000379267.2	G5E9D4
	ELP4	ENST00000379163.10	TSL:2	c.436G>A	p.Val146Ile	missense	Exon 4 of 11	ENSP00000368461.5	Q96EB1-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398156 Hom.: 0 Cov.: 27 AF XY: 0.00000144 AC XY: 1 AN XY: 693578

African (AFR) AF: 0.00 AC: 0 AN: 29656

American (AMR) AF: 0.00 AC: 0 AN: 32654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25026

East Asian (EAS) AF: 0.00 AC: 0 AN: 35026

South Asian (SAS) AF: 0.00 AC: 0 AN: 72896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086432

Other (OTH) AF: 0.00 AC: 0 AN: 57872

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.42
DANN	Benign	0.83
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.38
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.047
Sift	Benign	0.17	T
Sift4G	Benign	0.27	T
Polyphen		0.41	B
Vest4		0.043
MutPred		0.43		Gain of catalytic residue at V146 (P = 0.0315)
MVP		0.20
MPC		0.045
ClinPred		0.18	T
GERP RS		-1.1
Varity_R		0.038
gMVP		0.12
Mutation Taster		=96/4	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: rs144056743; hg19: chr11-31616371;