chr9-108929863-C-T

Position:

chr9-108929863-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 364581.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr9-108929863-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ELP1	NM_003640.5 linkuse as main transcript	c.209G>A	p.Arg70His	missense_variant	3/37	ENST00000374647.10
ELP1	XM_047423991.1 linkuse as main transcript	c.209G>A	p.Arg70His	missense_variant	3/25
ELP1	NM_001318360.2 linkuse as main transcript	c.-134G>A		5_prime_UTR_variant	3/37
ELP1	NM_001330749.2 linkuse as main transcript	c.-651G>A		5_prime_UTR_variant	3/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10 linkuse as main transcript	c.209G>A	p.Arg70His	missense_variant	3/37	1	NM_003640.5	P1

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

GnomAD3 exomes

AF:

0.00129

AC:

325

AN:

251492

Hom.:

AF XY:

0.00116

AC XY:

158

AN XY:

135920

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 SAS exome

AF:

0.000686

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

Gnomad4 AFR exome

AF:

0.00777

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0136

Gnomad4 SAS exome

AF:

0.000638

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000674

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.00242

AC:

369

AN:

152314

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00693

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0106

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000695

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ELP1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2019	- -

Familial dysautonomia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

ELP1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

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). -

Hereditary sensory and autonomic neuropathy

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

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

MutationTaster

Benign

1.0

N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over