rs78135392

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003640.5(ELP1):c.923T>C(p.Leu308Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000393 in 1,614,180 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L308L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 6.03

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008428782).

BP6

Variant 9-108916239-A-G is Benign according to our data. Variant chr9-108916239-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 364578.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ELP1	NM_003640.5 link	c.923T>C	p.Leu308Pro	missense_variant	Exon 10 of 37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2 link	c.581T>C	p.Leu194Pro	missense_variant	Exon 10 of 37		NP_001305289.1
ELP1	XM_047423991.1 link	c.923T>C	p.Leu308Pro	missense_variant	Exon 10 of 25		XP_047279947.1
ELP1	NM_001330749.2 link	c.-125T>C		5_prime_UTR_variant	Exon 8 of 35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10 link	c.923T>C	p.Leu308Pro	missense_variant	Exon 10 of 37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes

AF:

0.00217

AC:

331

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00740

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000541

AC:

136

AN:

251468

AF XY:

0.000412

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000208

AC:

304

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

135

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00678

AC:

227

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111972

Other (OTH)

AF:

0.000497

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00217

AC:

330

AN:

152340

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

159

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00736

AC:

306

AN:

41586

American (AMR)

AF:

0.00105

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000765

Hom.:

Bravo

AF:

0.00238

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial dysautonomia

Uncertain:2Benign:1

May 30, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

May 07, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ELP1 c.923T>C; p.Leu308Pro variant (rs78135392), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 364578). This variant is found in the African population with an allele frequency of 0.75% (186/24964 alleles, including a single homozygote) in the Genome Aggregation Database. The leucine at codon 308 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Leu308Pro variant is uncertain at this time. -

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ELP1-related disorder

Benign:1

Apr 26, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

M_CAP

Benign

0.023

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

PhyloP100

6.0

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.23

Sift

Uncertain

0.010

Sift4G

Benign

0.095

Polyphen

1.0

Vest4

0.64

MVP

0.71

MPC

0.49

ClinPred

0.037

GERP RS

5.6

Varity_R

0.61

gMVP

0.55

Mutation Taster

=36/64

disease causing

(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