rs148378319

Positions:

• chr9-108901650-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003640.5(ELP1):​c.1886G>A​(p.Arg629His) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,614,090 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (12 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 4.83

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]

ELP1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008384824).
• BP6: Variant 9-108901650-C-T is Benign according to our data. Variant chr9-108901650-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194739.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4}.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.1886G>A	p.Arg629His	missense_variant	17/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.1544G>A	p.Arg515His	missense_variant	17/37		NP_001305289.1
ELP1	NM_001330749.2	c.839G>A	p.Arg280His	missense_variant	15/35		NP_001317678.1
ELP1	XM_047423991.1	c.1886G>A	p.Arg629His	missense_variant	17/25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.1886G>A	p.Arg629His	missense_variant	17/37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00194 AC: 488 AN: 251240 Hom.: 0 AF XY: 0.00193 AC XY: 262 AN XY: 135766

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00270

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00273 AC: 3993 AN: 1461784 Hom.: 12 Cov.: 32 AF XY: 0.00279 AC XY: 2029 AN XY: 727198

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00478

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000846

Gnomad4 FIN exome AF: 0.00148

Gnomad4 NFE exome AF: 0.00312

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74492

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00300 Hom.: 1

Bravo AF: 0.00220

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00190 AC: 231

EpiCase AF: 0.00344

EpiControl AF: 0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2021	This variant is associated with the following publications: (PMID: 27582484) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ELP1: BP4, BS2 -

Familial dysautonomia Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2021	The ELP1 c.1886G>A; p.Arg629His variant (rs148378319), is reported in the literature in a cohort of Paclitaxel-induced peripheral neuropathy, but has been found in association with familial dysautonomia with no second variant detected (Apellaniz-Ruiz 2017). This variant is reported as uncertain significance or likely benign in ClinVar (Variation ID: 194739), and is found in the general population with an overall allele frequency of 0.019% (550/282,634 alleles) in the Genome Aggregation Database. The arginine at codon 629 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg629His variant is uncertain at this time. References: Apellaniz-Ruiz et al. Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy. Clin Cancer Res. 2017 Mar 1;23(5):1227-1235. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2018	Variant summary: IKBKAP c.1886G>A (p.Arg629His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 276958 control chromosomes. The observed variant frequency is slightly above the estimated maximal expected allele frequency for a pathogenic variant in IKBKAP causing Familial Dysautonomia phenotype (0.0018), suggesting that the variant may be benign. c.1886G>A has been reported in the literature in individuals affected with glioma and induced peripheral neuropathy, but not familial dysautonomia. Therefore, these reports do not provide unequivocal conclusions about an association of the variant with familial dysautonomia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with two classifying the variant as uncertain significance and one classifying at likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 19, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0084	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.076
Sift	Benign	0.15	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.35	B;.
Vest4		0.28
MVP		0.57
MPC		0.16
ClinPred		0.028	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs148378319; hg19: chr9-111663930; COSMIC: COSV65897820;