rs2230786

Positions:

• chr9-108929883-G-A
• chr9-108929883-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003640.5(ELP1):​c.189C>T​(p.Leu63=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,842 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L63L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (32 hom., cov: 32)
  • Exomes 𝑓: 0.022 (426 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0500

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 9-108929883-G-A is Benign according to our data. Variant chr9-108929883-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2732/152284) while in subpopulation NFE AF= 0.0246 (1674/68032). AF 95% confidence interval is 0.0236. There are 32 homozygotes in gnomad4. There are 1339 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.189C>T	p.Leu63=	synonymous_variant	3/37	ENST00000374647.10
ELP1	XM_047423991.1	c.189C>T	p.Leu63=	synonymous_variant	3/25
ELP1	NM_001318360.2	c.-154C>T		5_prime_UTR_variant	3/37
ELP1	NM_001330749.2	c.-671C>T		5_prime_UTR_variant	3/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.189C>T	p.Leu63=	synonymous_variant	3/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2723 AN: 152166 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0182 AC: 4566 AN: 251482 Hom.: 67 AF XY: 0.0185 AC XY: 2512 AN XY: 135914

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.00650

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00712

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0220 AC: 32184 AN: 1461558 Hom.: 426 Cov.: 31 AF XY: 0.0213 AC XY: 15494 AN XY: 727082

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.00653

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00749

Gnomad4 FIN exome AF: 0.0237

Gnomad4 NFE exome AF: 0.0253

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0179 AC: 2732 AN: 152284 Hom.: 32 Cov.: 32 AF XY: 0.0180 AC XY: 1339 AN XY: 74452

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.0239

Gnomad4 NFE AF: 0.0246

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0184 Hom.: 20

Bravo AF: 0.0167

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0239

EpiControl AF: 0.0202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Benign:2

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, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2023	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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	-0.43
CADD	Benign	5.6
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2230786; hg19: chr9-111692163;