rs2230794

chr9-108897159-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003640.5(ELP1):c.2490A>G(p.Ile830Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,613,950 control chromosomes in the GnomAD database, including 3,369 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (322 hom., cov: 32)
  • Exomes 𝑓: 0.055 (3047 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0970

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014864802).
• BP6: Variant 9-108897159-T-C is Benign according to our data. Variant chr9-108897159-T-C is described in ClinVar as [Benign]. Clinvar id is 137579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108897159-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.2490A>G	p.Ile830Met	missense_variant	23/37	ENST00000374647.10
ELP1	NM_001318360.2	c.2148A>G	p.Ile716Met	missense_variant	23/37
ELP1	NM_001330749.2	c.1443A>G	p.Ile481Met	missense_variant	21/35
ELP1	XM_047423991.1	c.2490A>G	p.Ile830Met	missense_variant	23/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.2490A>G	p.Ile830Met	missense_variant	23/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0525 AC: 7987 AN: 152136 Hom.: 320 Cov.: 32

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0565

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0508

Gnomad OTH AF: 0.0583

GnomAD3 exomes AF: 0.0744 AC: 18706 AN: 251332 Hom.: 1183 AF XY: 0.0684 AC XY: 9296 AN XY: 135828

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.0454

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.0464

Gnomad OTH exome AF: 0.0680

GnomAD4 exome AF: 0.0548 AC: 80079 AN: 1461694 Hom.: 3047 Cov.: 34 AF XY: 0.0533 AC XY: 38787 AN XY: 727172

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.114

Gnomad4 SAS exome AF: 0.0448

Gnomad4 FIN exome AF: 0.0956

Gnomad4 NFE exome AF: 0.0481

Gnomad4 OTH exome AF: 0.0533

GnomAD4 genome AF: 0.0525 AC: 7995 AN: 152256 Hom.: 322 Cov.: 32 AF XY: 0.0562 AC XY: 4187 AN XY: 74438

Gnomad4 AFR AF: 0.0145

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.0557

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0507

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0504 Hom.: 430

Bravo AF: 0.0548

TwinsUK AF: 0.0558 AC: 207

ALSPAC AF: 0.0470 AC: 181

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.0467 AC: 402

ExAC AF: 0.0672 AC: 8157

Asia WGS AF: 0.0940 AC: 324 AN: 3478

EpiCase AF: 0.0444

EpiControl AF: 0.0453

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2014	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. -

Familial dysautonomia Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	12
Dann	Benign	0.77
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.74	P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.13
Sift	Benign	0.19	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.57	P;.
Vest4		0.14
MPC		0.091
ClinPred		0.0079	T
GERP RS		-1.9
Varity_R		0.054
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs2230794; hg19: chr9-111659439; COSMIC: COSV65896856; COSMIC: COSV65896856;