rs1538660

Positions:

• chr9-108879545-G-A

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.3473C>T​(p.Pro1158Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,611,346 control chromosomes in the GnomAD database, including 28,307 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1158P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (4006 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24301 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.18

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=0.004501313).
• BP6: Variant 9-108879545-G-A is Benign according to our data. Variant chr9-108879545-G-A is described in ClinVar as [Benign]. Clinvar id is 259113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108879545-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.3473C>T	p.Pro1158Leu	missense_variant	33/37	ENST00000374647.10
ELP1	NM_001318360.2	c.3131C>T	p.Pro1044Leu	missense_variant	33/37
ELP1	NM_001330749.2	c.2426C>T	p.Pro809Leu	missense_variant	31/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.3473C>T	p.Pro1158Leu	missense_variant	33/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33017 AN: 151832 Hom.: 4003 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.194 AC: 48749 AN: 250972 Hom.: 5125 AF XY: 0.194 AC XY: 26290 AN XY: 135652

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.287

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.177 AC: 258332 AN: 1459392 Hom.: 24301 Cov.: 31 AF XY: 0.179 AC XY: 129759 AN XY: 726126

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.323

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.190

GnomAD4 genome AF: 0.217 AC: 33039 AN: 151954 Hom.: 4006 Cov.: 32 AF XY: 0.218 AC XY: 16182 AN XY: 74226

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.293

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.197

Alfa AF: 0.180 Hom.: 5911

Bravo AF: 0.220

TwinsUK AF: 0.160 AC: 594

ALSPAC AF: 0.172 AC: 663

ESP6500AA AF: 0.303 AC: 1333

ESP6500EA AF: 0.165 AC: 1423

ExAC AF: 0.198 AC: 24067

Asia WGS AF: 0.274 AC: 951 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.79
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.045
Sift	Benign	0.72	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0020	B;.
Vest4		0.084
MPC		0.074
ClinPred		0.0018	T
GERP RS		3.0
Varity_R		0.018
gMVP		0.43

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

Other links and lift over

dbSNP: rs1538660; hg19: chr9-111641825; COSMIC: COSV65896197;