rs12340246

Positions:

• chr9-108917592-G-A
• chr9-108917592-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003640.5(ELP1):​c.819C>T​(p.Leu273Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,613,602 control chromosomes in the GnomAD database, including 3,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (313 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2936 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.861

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-108917592-G-A is Benign according to our data. Variant chr9-108917592-G-A is described in ClinVar as [Benign]. Clinvar id is 137570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108917592-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.861 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.819C>T	p.Leu273Leu	synonymous_variant	9/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.477C>T	p.Leu159Leu	synonymous_variant	9/37		NP_001305289.1
ELP1	XM_047423991.1	c.819C>T	p.Leu273Leu	synonymous_variant	9/25		XP_047279947.1
ELP1	NM_001330749.2	c.-229C>T		5_prime_UTR_variant	7/35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.819C>T	p.Leu273Leu	synonymous_variant	9/37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes AF: 0.0513 AC: 7806 AN: 152050 Hom.: 311 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0555

Gnomad FIN AF: 0.0971

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0485

Gnomad OTH AF: 0.0566

GnomAD3 exomes AF: 0.0733 AC: 18430 AN: 251476 Hom.: 1186 AF XY: 0.0673 AC XY: 9145 AN XY: 135914

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.0438

Gnomad FIN exome AF: 0.0968

Gnomad NFE exome AF: 0.0444

Gnomad OTH exome AF: 0.0637

GnomAD4 exome AF: 0.0528 AC: 77165 AN: 1461432 Hom.: 2936 Cov.: 33 AF XY: 0.0514 AC XY: 37397 AN XY: 727048

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.0432

Gnomad4 FIN exome AF: 0.0908

Gnomad4 NFE exome AF: 0.0459

Gnomad4 OTH exome AF: 0.0512

GnomAD4 genome AF: 0.0513 AC: 7810 AN: 152170 Hom.: 313 Cov.: 32 AF XY: 0.0550 AC XY: 4092 AN XY: 74384

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.0547

Gnomad4 FIN AF: 0.0971

Gnomad4 NFE AF: 0.0485

Gnomad4 OTH AF: 0.0555

Alfa AF: 0.0448 Hom.: 280

Bravo AF: 0.0544

Asia WGS AF: 0.0860 AC: 298 AN: 3478

EpiCase AF: 0.0419

EpiControl AF: 0.0431

ClinVar

Significance: Benign

Submissions summary: Benign:7

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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 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	-	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.4
DANN	Benign	0.69

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: rs12340246; hg19: chr9-111679872; COSMIC: COSV65896328;