9-108897203-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

41 publications found

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 Gene-Disease associations (from GenCC):

primary dysautonomia
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
Riley-Day syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ELP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 137578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.224

AC:

56288

AN:

251272

AF XY:

0.215

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 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

African (AFR)

AF:

0.449

AC:

15045

AN:

33474

American (AMR)

AF:

0.285

AC:

12762

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0843

AC:

2203

AN:

26136

East Asian (EAS)

AF:

0.280

AC:

11134

AN:

39694

South Asian (SAS)

AF:

0.197

AC:

16952

AN:

86252

European-Finnish (FIN)

AF:

0.228

AC:

12182

AN:

53420

Middle Eastern (MID)

AF:

0.133

AC:

765

AN:

5768

European-Non Finnish (NFE)

AF:

0.187

AC:

208152

AN:

1111754

Other (OTH)

AF:

0.200

AC:

12096

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

13617

27234

40852

54469

68086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7548

15096

22644

30192

37740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.267

AC:

40515

AN:

151950

Hom.:

6431

Cov.:

AF XY:

0.267

AC XY:

19822

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.438

AC:

18127

AN:

41400

American (AMR)

AF:

0.242

AC:

3691

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0752

AC:

261

AN:

3472

East Asian (EAS)

AF:

0.272

AC:

1400

AN:

5150

South Asian (SAS)

AF:

0.215

AC:

1035

AN:

4810

European-Finnish (FIN)

AF:

0.239

AC:

2522

AN:

10564

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.187

AC:

12698

AN:

67974

Other (OTH)

AF:

0.233

AC:

492

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1426

2852

4277

5703

7129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

400

800

1200

1600

2000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.212

Hom.:

15241

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

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

1.8

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over