rs1140064

chr9-108916228-C-T

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.934G>A(p.Glu312Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0221 in 1,613,956 control chromosomes in the GnomAD database, including 478 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (43 hom., cov: 33)
  • Exomes 𝑓: 0.022 (435 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.65

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=0.0025151968).
• BP6: Variant 9-108916228-C-T is Benign according to our data. Variant chr9-108916228-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108916228-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0211 (3212/152316) while in subpopulation NFE AF= 0.0247 (1678/68028). AF 95% confidence interval is 0.0237. There are 43 homozygotes in gnomad4. There are 1576 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.934G>A	p.Glu312Lys	missense_variant	10/37	ENST00000374647.10
ELP1	NM_001318360.2	c.592G>A	p.Glu198Lys	missense_variant	10/37
ELP1	XM_047423991.1	c.934G>A	p.Glu312Lys	missense_variant	10/25
ELP1	NM_001330749.2	c.-114G>A		5_prime_UTR_variant	8/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.934G>A	p.Glu312Lys	missense_variant	10/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3200 AN: 152198 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0189 AC: 4765 AN: 251452 Hom.: 72 AF XY: 0.0192 AC XY: 2603 AN XY: 135888

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00737

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00715

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0223 AC: 32522 AN: 1461640 Hom.: 435 Cov.: 31 AF XY: 0.0215 AC XY: 15645 AN XY: 727138

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00740

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00750

Gnomad4 FIN exome AF: 0.0238

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0189

GnomAD4 genome AF: 0.0211 AC: 3212 AN: 152316 Hom.: 43 Cov.: 33 AF XY: 0.0212 AC XY: 1576 AN XY: 74474

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.0238

Gnomad4 NFE AF: 0.0247

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0230 Hom.: 93

Bravo AF: 0.0200

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.0226 AC: 194

ExAC AF: 0.0204 AC: 2483

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0240

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

Likely 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 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, 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	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 14, 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	-0.65	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.048
Sift	Benign	0.36	T
Sift4G	Benign	0.50	T
Polyphen		0.075	B
Vest4		0.050
MPC		0.10
ClinPred		0.016	T
GERP RS		4.7
Varity_R		0.046
gMVP		0.18

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: rs1140064; hg19: chr9-111678508;