9-108906372-C-T

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.1574G>A(p.Arg525Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 1,613,862 control chromosomes in the GnomAD database, including 3,364 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R525W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.070 (478 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2886 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.301

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=0.0019468963).
• BP6: Variant 9-108906372-C-T is Benign according to our data. Variant chr9-108906372-C-T is described in ClinVar as [Benign]. Clinvar id is 137574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108906372-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.1574G>A	p.Arg525Gln	missense_variant	14/37	ENST00000374647.10
ELP1	NM_001318360.2	c.1232G>A	p.Arg411Gln	missense_variant	14/37
ELP1	NM_001330749.2	c.527G>A	p.Arg176Gln	missense_variant	12/35
ELP1	XM_047423991.1	c.1574G>A	p.Arg525Gln	missense_variant	14/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.1574G>A	p.Arg525Gln	missense_variant	14/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0697 AC: 10604 AN: 152080 Hom.: 480 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0617

Gnomad OTH AF: 0.0624

GnomAD3 exomes AF: 0.0511 AC: 12831 AN: 251282 Hom.: 432 AF XY: 0.0504 AC XY: 6849 AN XY: 135806

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0243

Gnomad FIN exome AF: 0.0685

Gnomad NFE exome AF: 0.0618

Gnomad OTH exome AF: 0.0506

GnomAD4 exome AF: 0.0587 AC: 85735 AN: 1461664 Hom.: 2886 Cov.: 31 AF XY: 0.0577 AC XY: 41960 AN XY: 727150

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.0382

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0257

Gnomad4 FIN exome AF: 0.0656

Gnomad4 NFE exome AF: 0.0636

Gnomad4 OTH exome AF: 0.0543

GnomAD4 genome AF: 0.0697 AC: 10601 AN: 152198 Hom.: 478 Cov.: 32 AF XY: 0.0684 AC XY: 5092 AN XY: 74416

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0487

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.0734

Gnomad4 NFE AF: 0.0617

Gnomad4 OTH AF: 0.0617

Alfa AF: 0.0602 Hom.: 737

Bravo AF: 0.0717

TwinsUK AF: 0.0604 AC: 224

ALSPAC AF: 0.0724 AC: 279

ESP6500AA AF: 0.113 AC: 500

ESP6500EA AF: 0.0636 AC: 547

ExAC AF: 0.0542 AC: 6583

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.0607

EpiControl AF: 0.0606

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	6.0
Dann	Benign	0.63
DEOGEN2	Benign	0.029	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.7	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.24	N;N
REVEL	Benign	0.0080
Sift	Benign	0.71	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0	B;.
Vest4		0.051
MPC		0.081
ClinPred		0.00059	T
GERP RS		0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.010
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs838827; hg19: chr9-111668652; COSMIC: COSV65899988;