rs17853166

chr9-108917660-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003640.5(ELP1):c.751A>G(p.Ser251Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0212 in 1,612,468 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (30 hom., cov: 32)
  • Exomes 𝑓: 0.022 (422 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.58

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=0.012105852).
• BP6: Variant 9-108917660-T-C is Benign according to our data. Variant chr9-108917660-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 137569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108917660-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.016 (2405/150776) while in subpopulation NFE AF= 0.0248 (1678/67570). AF 95% confidence interval is 0.0238. There are 30 homozygotes in gnomad4. There are 1175 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.751A>G	p.Ser251Gly	missense_variant	9/37	ENST00000374647.10
ELP1	NM_001318360.2	c.409A>G	p.Ser137Gly	missense_variant	9/37
ELP1	XM_047423991.1	c.751A>G	p.Ser251Gly	missense_variant	9/25
ELP1	NM_001330749.2	c.-297A>G		5_prime_UTR_variant	7/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.751A>G	p.Ser251Gly	missense_variant	9/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2404 AN: 150658 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0119

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00795

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0116

GnomAD3 exomes AF: 0.0176 AC: 4435 AN: 251482 Hom.: 67 AF XY: 0.0182 AC XY: 2469 AN XY: 135916

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00706

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0218 AC: 31808 AN: 1461692 Hom.: 422 Cov.: 33 AF XY: 0.0211 AC XY: 15325 AN XY: 727164

Gnomad4 AFR exome AF: 0.00421

Gnomad4 AMR exome AF: 0.00631

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00747

Gnomad4 FIN exome AF: 0.0238

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0175

GnomAD4 genome AF: 0.0160 AC: 2405 AN: 150776 Hom.: 30 Cov.: 32 AF XY: 0.0160 AC XY: 1175 AN XY: 73656

Gnomad4 AFR AF: 0.00438

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.0119

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00796

Gnomad4 FIN AF: 0.0239

Gnomad4 NFE AF: 0.0248

Gnomad4 OTH AF: 0.0115

Alfa AF: 0.0216 Hom.: 105

Bravo AF: 0.0145

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0227 AC: 195

ExAC AF: 0.0188 AC: 2288

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0239

EpiControl AF: 0.0202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.21
Sift	Uncertain	0.016	D
Sift4G	Benign	0.11	T
Polyphen		0.95	P
Vest4		0.059
MPC		0.089
ClinPred		0.061	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.21

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: rs17853166; hg19: chr9-111679940;