chr9-108906372-C-T

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.1574G>A(p.Arg525Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 1,613,862 control chromosomes in the GnomAD database, including 3,364 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R525W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.070 ( 478 hom., cov: 32)

Exomes 𝑓: 0.059 ( 2886 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.301

Publications

19 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=0.0019468963).

BP6

Variant 9-108906372-C-T is Benign according to our data. Variant chr9-108906372-C-T is described in ClinVar as Benign. ClinVar VariationId is 137574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003640.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELP1	NM_003640.5	MANE Select	c.1574G>A	p.Arg525Gln	missense	Exon 14 of 37	NP_003631.2
ELP1	NM_001318360.2		c.1232G>A	p.Arg411Gln	missense	Exon 14 of 37	NP_001305289.1
ELP1	NM_001330749.2		c.527G>A	p.Arg176Gln	missense	Exon 12 of 35	NP_001317678.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELP1	ENST00000374647.10	TSL:1 MANE Select	c.1574G>A	p.Arg525Gln	missense	Exon 14 of 37	ENSP00000363779.5
ELP1	ENST00000537196.1	TSL:1	c.527G>A	p.Arg176Gln	missense	Exon 7 of 30	ENSP00000439367.1
ELP1	ENST00000495759.6	TSL:1	n.*184G>A		non_coding_transcript_exon	Exon 8 of 31	ENSP00000433514.2

Frequencies

GnomAD3 genomes

AF:

0.0697

AC:

10604

AN:

152080

Hom.:

480

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.0489

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0232

Gnomad FIN

AF:

0.0734

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0617

Gnomad OTH

AF:

0.0624

GnomAD2 exomes

AF:

0.0511

AC:

12831

AN:

251282

AF XY:

0.0504

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.0358

Gnomad ASJ exome

AF:

0.0175

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0685

Gnomad NFE exome

AF:

0.0618

Gnomad OTH exome

AF:

0.0506

GnomAD4 exome

AF:

0.0587

AC:

85735

AN:

1461664

Hom.:

2886

Cov.:

AF XY:

0.0577

AC XY:

41960

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.109

AC:

3660

AN:

33464

American (AMR)

AF:

0.0382

AC:

1706

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0171

AC:

448

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39694

South Asian (SAS)

AF:

0.0257

AC:

2219

AN:

86252

European-Finnish (FIN)

AF:

0.0656

AC:

3504

AN:

53418

Middle Eastern (MID)

AF:

0.0338

AC:

195

AN:

5768

European-Non Finnish (NFE)

AF:

0.0636

AC:

70718

AN:

1111840

Other (OTH)

AF:

0.0543

AC:

3279

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

4229

8459

12688

16918

21147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2616

5232

7848

10464

13080

<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:

0.0697

AC:

10601

AN:

152198

Hom.:

478

Cov.:

AF XY:

0.0684

AC XY:

5092

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.110

AC:

4555

AN:

41500

American (AMR)

AF:

0.0487

AC:

745

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5190

South Asian (SAS)

AF:

0.0230

AC:

111

AN:

4818

European-Finnish (FIN)

AF:

0.0734

AC:

778

AN:

10596

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0617

AC:

4199

AN:

68022

Other (OTH)

AF:

0.0617

AC:

130

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

513

1025

1538

2050

2563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0629

Hom.:

1177

Bravo

AF:

0.0717

TwinsUK

AF:

0.0604

AC:

224

ALSPAC

AF:

0.0724

AC:

279

ESP6500AA

AF:

0.113

AC:

500

ESP6500EA

AF:

0.0636

AC:

547

ExAC

AF:

0.0542

AC:

6583

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0607

EpiControl

AF:

0.0606

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial dysautonomia (3)

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.0

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.029

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.7

PhyloP100

0.30

PrimateAI

Benign

0.19

PROVEAN

Benign

0.24

REVEL

Benign

0.0080

Sift

Benign

0.71

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.051

MPC

0.081

ClinPred

0.00059

GERP RS

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.010

gMVP

0.14

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over