chr9-108929863-C-T

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.209G>A(p.Arg70His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000866 in 1,613,894 control chromosomes in the GnomAD database, including 9 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 7 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.0900

Publications

6 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=0.00657627).

BP6

Variant 9-108929863-C-T is Benign according to our data. Variant chr9-108929863-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 364581.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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.209G>A	p.Arg70His	missense	Exon 3 of 37	NP_003631.2
ELP1	NM_001318360.2		c.-134G>A		5_prime_UTR	Exon 3 of 37	NP_001305289.1
ELP1	NM_001330749.2		c.-651G>A		5_prime_UTR	Exon 3 of 35	NP_001317678.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELP1	ENST00000374647.10	TSL:1 MANE Select	c.209G>A	p.Arg70His	missense	Exon 3 of 37	ENSP00000363779.5
ELP1	ENST00000537196.1	TSL:1	c.-308+4001G>A		intron	N/A	ENSP00000439367.1
ELP1	ENST00000495759.6	TSL:1	n.209G>A		non_coding_transcript_exon	Exon 3 of 31	ENSP00000433514.2

Frequencies

GnomAD3 genomes

AF:

0.00242

AC:

369

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00695

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0106

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00129

AC:

325

AN:

251492

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.00750

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00799

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000704

AC:

1029

AN:

1461580

Hom.:

Cov.:

AF XY:

0.000678

AC XY:

493

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.00777

AC:

260

AN:

33470

American (AMR)

AF:

0.000514

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0136

AC:

541

AN:

39698

South Asian (SAS)

AF:

0.000638

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000538

AC:

AN:

5578

European-Non Finnish (NFE)

AF:

0.0000674

AC:

AN:

1111954

Other (OTH)

AF:

0.00118

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00242

AC:

369

AN:

152314

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00693

AC:

288

AN:

41582

American (AMR)

AF:

0.000850

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0106

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68020

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00295

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00150

AC:

182

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

ELP1-related disorder (1)

Familial dysautonomia (1)

Hereditary sensory and autonomic neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.026

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

-0.090

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.73

REVEL

Benign

0.029

Sift

Benign

0.61

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.031

MVP

0.15

MPC

0.087

ClinPred

0.0020

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.19

Mutation Taster

=98/2

polymorphism

(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

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