NM_003640.5:c.2446A>C

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.2446A>C(p.Ile816Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,613,558 control chromosomes in the GnomAD database, including 37,443 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 0.27 ( 6431 hom., cov: 32)

Exomes 𝑓: 0.20 ( 31012 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.83

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=7.942915E-4).

BP6

Variant 9-108897203-T-G is Benign according to our data. Variant chr9-108897203-T-G is described in ClinVar as [Benign]. Clinvar id is 137578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108897203-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5 link	c.2446A>C	p.Ile816Leu	missense_variant	Exon 23 of 37	ENST00000374647.10	NP_003631.2	O95163Q4LE38Q8N516
ELP1	NM_001318360.2 link	c.2104A>C	p.Ile702Leu	missense_variant	Exon 23 of 37		NP_001305289.1	O95163A0A6Q8PGW3B4E3I9
ELP1	NM_001330749.2 link	c.1399A>C	p.Ile467Leu	missense_variant	Exon 21 of 35		NP_001317678.1	F5H2T0B3KNB2
ELP1	XM_047423991.1 link	c.2446A>C	p.Ile816Leu	missense_variant	Exon 23 of 25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10 link	c.2446A>C	p.Ile816Leu	missense_variant	Exon 23 of 37	1	NM_003640.5	ENSP00000363779.5		O95163

Frequencies

GnomAD3 genomes

AF:

0.267

AC:

40468

AN:

151832

Hom.:

6420

Cov.:

show subpopulations

Gnomad AFR

AF:

0.438

Gnomad AMI

AF:

0.267

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.0752

Gnomad EAS

AF:

0.272

Gnomad SAS

AF:

0.217

Gnomad FIN

AF:

0.239

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.235

GnomAD3 exomes

AF:

0.224

AC:

56288

AN:

251272

Hom.:

7069

AF XY:

0.215

AC XY:

29228

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.450

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.0841

Gnomad EAS exome

AF:

0.269

Gnomad SAS exome

AF:

0.199

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.184

Gnomad OTH exome

AF:

0.196

GnomAD4 exome

AF:

0.199

AC:

291291

AN:

1461608

Hom.:

31012

Cov.:

AF XY:

0.198

AC XY:

143630

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.449

Gnomad4 AMR exome

AF:

0.285

Gnomad4 ASJ exome

AF:

0.0843

Gnomad4 EAS exome

AF:

0.280

Gnomad4 SAS exome

AF:

0.197

Gnomad4 FIN exome

AF:

0.228

Gnomad4 NFE exome

AF:

0.187

Gnomad4 OTH exome

AF:

0.200

GnomAD4 genome

AF:

0.267

AC:

40515

AN:

151950

Hom.:

6431

Cov.:

AF XY:

0.267

AC XY:

19822

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.438

Gnomad4 AMR

AF:

0.242

Gnomad4 ASJ

AF:

0.0752

Gnomad4 EAS

AF:

0.272

Gnomad4 SAS

AF:

0.215

Gnomad4 FIN

AF:

0.239

Gnomad4 NFE

AF:

0.187

Gnomad4 OTH

AF:

0.233

Alfa

AF:

0.198

Hom.:

8651

Bravo

AF:

0.280

TwinsUK

AF:

0.190

AC:

705

ALSPAC

AF:

0.198

AC:

765

ESP6500AA

AF:

0.441

AC:

1945

ESP6500EA

AF:

0.183

AC:

1575

ExAC

AF:

0.227

AC:

27570

Asia WGS

AF:

0.266

AC:

923

AN:

3478

EpiCase

AF:

0.175

EpiControl

AF:

0.174

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial dysautonomia

Benign:3

Jan 12, 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. -

May 10, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Jan 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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.088

T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.39

T;T

MetaRNN

Benign

0.00079

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.33

N;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.073

Sift

Benign

0.36

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.0

B;.

Vest4

0.11

MutPred

0.35

Loss of methylation at K815 (P = 0.0878);.;

MPC

0.071

ClinPred

0.0040

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.46

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

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