9-108898700-G-T

Variant names:

• chr9-108898700-G-T
• rs182287137
• NM_003640.5:c.2254C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003640.5(ELP1):​c.2254C>A​(p.Leu752Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.94

Genes affected

ELP1 (HGNC:5959): (elongator acetyltransferase complex subunit 1) The protein encoded by this gene is a scaffold protein and a regulator for three different kinases involved in proinflammatory signaling. The encoded protein can bind NF-kappa-B-inducing kinase and I-kappa-B kinases through separate domains and assemble them into an active kinase complex. Mutations in this gene have been associated with familial dysautonomia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5	c.2254C>A	p.Leu752Ile	missense_variant	Exon 21 of 37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.1912C>A	p.Leu638Ile	missense_variant	Exon 21 of 37		NP_001305289.1
ELP1	NM_001330749.2	c.1207C>A	p.Leu403Ile	missense_variant	Exon 19 of 35		NP_001317678.1
ELP1	XM_047423991.1	c.2254C>A	p.Leu752Ile	missense_variant	Exon 21 of 25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.2254C>A	p.Leu752Ile	missense_variant	Exon 21 of 37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial dysautonomia Uncertain:1

Jul 12, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 21, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a IKBKAP-related disease. This sequence change replaces leucine with isoleucine at codon 752 of the IKBKAP protein (p.Leu752Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.091	T;T
Sift4G	Benign	0.083	T;T
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.89		Gain of methylation at K747 (P = 0.0481);.;
MVP		0.60
MPC		0.44
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.37
gMVP		0.36

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: rs182287137; hg19: chr9-111660980;