chr9-108891294-C-G

Position:

• chr9-108891294-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_003640.5(ELP1):​c.3069G>C​(p.Leu1023Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,613,932 control chromosomes in the GnomAD database, including 151,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10889 hom., cov: 33)
  • Exomes 𝑓: 0.43 (140588 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.25

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]

ELP1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-108891294-C-G is Benign according to our data. Variant chr9-108891294-C-G is described in ClinVar as [Benign]. Clinvar id is 259111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108891294-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.3069G>C	p.Leu1023Leu	synonymous_variant	28/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.2727G>C	p.Leu909Leu	synonymous_variant	28/37		NP_001305289.1
ELP1	NM_001330749.2	c.2022G>C	p.Leu674Leu	synonymous_variant	26/35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.3069G>C	p.Leu1023Leu	synonymous_variant	28/37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52791 AN: 152014 Hom.: 10883 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.396

GnomAD3 exomes AF: 0.402 AC: 100781 AN: 250962 Hom.: 21422 AF XY: 0.403 AC XY: 54612 AN XY: 135654

Gnomad AFR exome AF: 0.0943

Gnomad AMR exome AF: 0.418

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.452

Gnomad SAS exome AF: 0.314

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.433 AC: 633540 AN: 1461798 Hom.: 140588 Cov.: 55 AF XY: 0.431 AC XY: 313407 AN XY: 727200

Gnomad4 AFR exome AF: 0.0909

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.490

Gnomad4 EAS exome AF: 0.421

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.426

GnomAD4 genome AF: 0.347 AC: 52804 AN: 152134 Hom.: 10889 Cov.: 33 AF XY: 0.347 AC XY: 25765 AN XY: 74348

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.448

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.401

Alfa AF: 0.338 Hom.: 1672

Bravo AF: 0.341

Asia WGS AF: 0.347 AC: 1207 AN: 3478

EpiCase AF: 0.447

EpiControl AF: 0.457

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.8
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs1063110; hg19: chr9-111653574; COSMIC: COSV65896937; COSMIC: COSV65896937;