rs145484092

chr9-108894000-T-Achr9-108894000-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003640.5(ELP1):c.2803A>T(p.Thr935Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,605,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T935A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 4.04

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25970033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.2803A>T	p.Thr935Ser	missense_variant	26/37	ENST00000374647.10
ELP1	NM_001318360.2	c.2461A>T	p.Thr821Ser	missense_variant	26/37
ELP1	NM_001330749.2	c.1756A>T	p.Thr586Ser	missense_variant	24/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.2803A>T	p.Thr935Ser	missense_variant	26/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152172 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 251036 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135678

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: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1453060 Hom.: 0 Cov.: 28 AF XY: 0.000119 AC XY: 86 AN XY: 723528

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: 0.000154

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 15, 2017	The p.Thr935Ser variant (rs14548409) has been reported as a variant of uncertain significance that was detected twice in a large cohort of patients with idiopathic peripheral neuropathy (Antoniardi 2015). This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 364564). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in European populations of 0.008% (identified on 10 out of 126,420 chromosomes). The threonine at codon 935 is moderately conserved (Alamut software v2.9.0), however several species including cape golden mole, lizard, Atlantic cod and lamprey have a serine at this position, suggesting this change may be evolutionary tolerated. Computational analyses return mixed predictions regarding the effect on IKBKAP protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing). -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2022	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 935 of the ELP1 protein (p.Thr935Ser). This variant is present in population databases (rs145484092, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 364564). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. -

Familial dysautonomia Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2022

The c.2803A>T (p.T935S) alteration is located in exon 26 (coding exon 25) of the IKBKAP gene. This alteration results from a A to T substitution at nucleotide position 2803, causing the threonine (T) at amino acid position 935 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Medulloblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Dec 19, 2022

The ELP1 c.2803A>T (p.Thr935Ser) missense change has a maximum subpopulation frequency of 0.0078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with Charcot-Marie-Tooth disease and in an individual with hereditary motor neuropathy (PMID: 26392352). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-0.046
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.14
Sift	Benign	0.43	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.17	B;.
Vest4		0.16
MutPred		0.50		Gain of loop (P = 0.1069);.;
MVP		0.49
MPC		0.16
ClinPred		0.13	T
GERP RS		5.9
Varity_R		0.20
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs145484092; hg19: chr9-111656280;