rs2230798

chr9-108893948-T-Achr9-108893948-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003640.5(ELP1):c.2855A>T(p.Lys952Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,613,514 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K952Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (15 hom., cov: 32)
  • Exomes 𝑓: 0.018 (350 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.51

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010479808).
• BP6: Variant 9-108893948-T-A is Benign according to our data. Variant chr9-108893948-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 259109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108893948-T-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.2855A>T	p.Lys952Ile	missense_variant	26/37	ENST00000374647.10
ELP1	NM_001318360.2	c.2513A>T	p.Lys838Ile	missense_variant	26/37
ELP1	NM_001330749.2	c.1808A>T	p.Lys603Ile	missense_variant	24/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.2855A>T	p.Lys952Ile	missense_variant	26/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2075 AN: 152162 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0255

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0157 AC: 3954 AN: 251192 Hom.: 49 AF XY: 0.0152 AC XY: 2060 AN XY: 135746

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0290

Gnomad SAS exome AF: 0.00461

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0182 AC: 26614 AN: 1461234 Hom.: 350 Cov.: 30 AF XY: 0.0177 AC XY: 12874 AN XY: 726932

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.0544

Gnomad4 SAS exome AF: 0.00510

Gnomad4 FIN exome AF: 0.0268

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0136 AC: 2072 AN: 152280 Hom.: 15 Cov.: 32 AF XY: 0.0135 AC XY: 1004 AN XY: 74478

Gnomad4 AFR AF: 0.00347

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0323

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0255

Gnomad4 NFE AF: 0.0180

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0147 Hom.: 17

Bravo AF: 0.0126

TwinsUK AF: 0.0224 AC: 83

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0160 AC: 138

ExAC AF: 0.0160 AC: 1946

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2019	Variant summary: IKBKAP c.2855A>T (p.Lys952Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.016 in 276918 control chromosomes in the gnomAD database, including 53 homozygotes. The observed variant frequency is approximately 8.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in IKBKAP causing Familial Dysautonomia phenotype (0.0018), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2855A>T in individuals affected with Familial Dysautonomia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Familial dysautonomia Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 30, 2018	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	0.79	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		1.0	D;.
Vest4		0.44
MPC		0.54
ClinPred		0.082	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.47

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: rs2230798; hg19: chr9-111656228; COSMIC: COSV65897871; COSMIC: COSV65897871;