rs10521092

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.545T>A(p.Met182Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0112 in 1,613,242 control chromosomes in the GnomAD database, including 1,875 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M182I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.060 ( 935 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 940 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.16

Publications

7 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=0.0010724664).

BP6

Variant 9-108922849-A-T is Benign according to our data. Variant chr9-108922849-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5 link	c.545T>A	p.Met182Lys	missense_variant	Exon 6 of 37	ENST00000374647.10	NP_003631.2	O95163Q4LE38Q8N516
ELP1	NM_001318360.2 link	c.203T>A	p.Met68Lys	missense_variant	Exon 6 of 37		NP_001305289.1	O95163A0A6Q8PGW3B4E3I9
ELP1	XM_047423991.1 link	c.545T>A	p.Met182Lys	missense_variant	Exon 6 of 25		XP_047279947.1
ELP1	NM_001330749.2 link	c.-315T>A		5_prime_UTR_variant	Exon 6 of 35		NP_001317678.1	F5H2T0B3KNB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10 link	c.545T>A	p.Met182Lys	missense_variant	Exon 6 of 37	1	NM_003640.5	ENSP00000363779.5		O95163

Frequencies

GnomAD3 genomes

AF:

0.0602

AC:

9152

AN:

152144

Hom.:

935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0176

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0415

GnomAD2 exomes

AF:

0.0156

AC:

3928

AN:

251422

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.00798

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00607

AC:

8868

AN:

1460980

Hom.:

940

Cov.:

AF XY:

0.00515

AC XY:

3747

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.226

AC:

7548

AN:

33400

American (AMR)

AF:

0.00923

AC:

413

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000336

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000122

AC:

136

AN:

1111254

Other (OTH)

AF:

0.0116

AC:

703

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

372

745

1117

1490

1862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

208

416

624

832

1040

<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:

0.0602

AC:

9171

AN:

152262

Hom.:

935

Cov.:

AF XY:

0.0579

AC XY:

4314

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.212

AC:

8791

AN:

41506

American (AMR)

AF:

0.0175

AC:

268

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68034

Other (OTH)

AF:

0.0411

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

363

726

1088

1451

1814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.00934

Hom.:

112

Bravo

AF:

0.0691

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.213

AC:

940

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0197

AC:

2393

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial dysautonomia

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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. -

not specified

Benign:2

May 01, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

0.084

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.021

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0011

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.99

PhyloP100

4.2

PrimateAI

Benign

0.31

PROVEAN

Benign

2.3

REVEL

Benign

0.070

Sift

Benign

0.38

Sift4G

Benign

0.97

Polyphen

0.0

Vest4

0.042

MPC

0.11

ClinPred

0.026

GERP RS

4.4

Varity_R

0.21

gMVP

0.21

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