rs17853166

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003640.5(ELP1):c.751A>G(p.Ser251Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0212 in 1,612,468 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 30 hom., cov: 32)

Exomes 𝑓: 0.022 ( 422 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.58

Publications

12 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=0.012105852).

BP6

Variant 9-108917660-T-C is Benign according to our data. Variant chr9-108917660-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.016 (2405/150776) while in subpopulation NFE AF = 0.0248 (1678/67570). AF 95% confidence interval is 0.0238. There are 30 homozygotes in GnomAd4. There are 1175 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5 link	c.751A>G	p.Ser251Gly	missense_variant	Exon 9 of 37	ENST00000374647.10	NP_003631.2	O95163Q4LE38Q8N516
ELP1	NM_001318360.2 link	c.409A>G	p.Ser137Gly	missense_variant	Exon 9 of 37		NP_001305289.1	O95163A0A6Q8PGW3B4E3I9
ELP1	XM_047423991.1 link	c.751A>G	p.Ser251Gly	missense_variant	Exon 9 of 25		XP_047279947.1
ELP1	NM_001330749.2 link	c.-297A>G		5_prime_UTR_variant	Exon 7 of 35		NP_001317678.1	F5H2T0B3KNB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10 link	c.751A>G	p.Ser251Gly	missense_variant	Exon 9 of 37	1	NM_003640.5	ENSP00000363779.5		O95163

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2404

AN:

150658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00437

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.0119

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00795

Gnomad FIN

AF:

0.0239

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0248

Gnomad OTH

AF:

0.0116

GnomAD2 exomes

AF:

0.0176

AC:

4435

AN:

251482

AF XY:

0.0182

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0243

Gnomad NFE exome

AF:

0.0279

Gnomad OTH exome

AF:

0.0194

GnomAD4 exome

AF:

0.0218

AC:

31808

AN:

1461692

Hom.:

422

Cov.:

AF XY:

0.0211

AC XY:

15325

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00421

AC:

141

AN:

33480

American (AMR)

AF:

0.00631

AC:

282

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0123

AC:

321

AN:

26132

East Asian (EAS)

AF:

0.000126

AC:

AN:

39690

South Asian (SAS)

AF:

0.00747

AC:

644

AN:

86256

European-Finnish (FIN)

AF:

0.0238

AC:

1269

AN:

53412

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0252

AC:

28032

AN:

1111840

Other (OTH)

AF:

0.0175

AC:

1056

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1505

3010

4515

6020

7525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1002

2004

3006

4008

5010

<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:

0.0160

AC:

2405

AN:

150776

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1175

AN XY:

73656

show subpopulations

African (AFR)

AF:

0.00438

AC:

179

AN:

40876

American (AMR)

AF:

0.0119

AC:

180

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.0119

AC:

AN:

3438

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00796

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.0239

AC:

251

AN:

10484

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0248

AC:

1678

AN:

67570

Other (OTH)

AF:

0.0115

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

119

239

358

478

597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0218

Hom.:

230

Bravo

AF:

0.0145

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0270

AC:

104

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0227

AC:

195

ExAC

AF:

0.0188

AC:

2288

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0239

EpiControl

AF:

0.0202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial dysautonomia

Benign:4

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 28, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 03, 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:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.68

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.3

PhyloP100

3.6

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.21

Sift

Uncertain

0.016

Sift4G

Benign

0.11

Polyphen

0.95

Vest4

0.059

MPC

0.089

ClinPred

0.061

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.21

Mutation Taster

=79/21

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