9-108906372-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.070 ( 478 hom., cov: 32)

Exomes 𝑓: 0.059 ( 2886 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.301

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ELP1	NM_003640.5 link	c.1574G>A	p.Arg525Gln	missense_variant	Exon 14 of 37	ENST00000374647.10	NP_003631.2	O95163Q4LE38Q8N516
ELP1	NM_001318360.2 link	c.1232G>A	p.Arg411Gln	missense_variant	Exon 14 of 37		NP_001305289.1	O95163A0A6Q8PGW3B4E3I9
ELP1	NM_001330749.2 link	c.527G>A	p.Arg176Gln	missense_variant	Exon 12 of 35		NP_001317678.1	F5H2T0B3KNB2
ELP1	XM_047423991.1 link	c.1574G>A	p.Arg525Gln	missense_variant	Exon 14 of 25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10 link	c.1574G>A	p.Arg525Gln	missense_variant	Exon 14 of 37	1	NM_003640.5	ENSP00000363779.5		O95163

Frequencies

GnomAD3 genomes

AF:

0.0697

AC:

10604

AN:

152080

Hom.:

480

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0577

AC XY:

41960

AN XY:

727150

show subpopulations

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.:

AF XY:

0.0684

AC XY:

5092

AN XY:

74416

show subpopulations

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:

AN:

3478

EpiCase

AF:

0.0607

EpiControl

AF:

0.0606

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial dysautonomia

Benign:3

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.72

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

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.7

N;.

PrimateAI

Benign

0.19

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over