rs2275495

chr9-108882116-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.3285+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,610,484 control chromosomes in the GnomAD database, including 15,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3203 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12203 hom.)
• Consequence: ELP1 NM_003640.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.47

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 (BayesDel_noAF=-0.84).
• BP6: Variant 9-108882116-G-A is Benign according to our data. Variant chr9-108882116-G-A is described in ClinVar as [Benign]. Clinvar id is 137582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108882116-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.3285+9C>T		intron_variant		ENST00000374647.10
ELP1	NM_001318360.2	c.2943+9C>T		intron_variant
ELP1	NM_001330749.2	c.2238+9C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.3285+9C>T		intron_variant		1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27408 AN: 151914 Hom.: 3199 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.161

GnomAD3 exomes AF: 0.143 AC: 35712 AN: 250548 Hom.: 3235 AF XY: 0.133 AC XY: 17959 AN XY: 135468

Gnomad AFR exome AF: 0.337

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.0368

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.0918

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.120 AC: 175196 AN: 1458452 Hom.: 12203 Cov.: 30 AF XY: 0.118 AC XY: 85356 AN XY: 725754

Gnomad4 AFR exome AF: 0.338

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.0367

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.0936

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.180 AC: 27433 AN: 152032 Hom.: 3203 Cov.: 32 AF XY: 0.181 AC XY: 13455 AN XY: 74334

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.174

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.159

Alfa AF: 0.146 Hom.: 1264

Bravo AF: 0.193

Asia WGS AF: 0.124 AC: 432 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.106

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	GeneDx	Mar 07, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial dysautonomia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 09, 2017	- -
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. -

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
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.55
Dann	Benign	0.49

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: rs2275495; hg19: chr9-111644396; COSMIC: COSV65896849;