rs2230788

Positions:

• chr9-108926548-C-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.441G>A​(p.Gln147=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0901 in 1,611,970 control chromosomes in the GnomAD database, including 6,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (585 hom., cov: 32)
  • Exomes 𝑓: 0.091 (6340 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.05

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 9-108926548-C-T is Benign according to our data. Variant chr9-108926548-C-T is described in ClinVar as [Benign]. Clinvar id is 137583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108926548-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.441G>A	p.Gln147=	synonymous_variant	5/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.99G>A	p.Gln33=	synonymous_variant	5/37		NP_001305289.1
ELP1	XM_047423991.1	c.441G>A	p.Gln147=	synonymous_variant	5/25		XP_047279947.1
ELP1	NM_001330749.2	c.-419G>A		5_prime_UTR_variant	5/35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.441G>A	p.Gln147=	synonymous_variant	5/37	1	NM_003640.5	ENSP00000363779	P1

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12367 AN: 152112 Hom.: 585 Cov.: 32

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.0857

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0908

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0911

Gnomad OTH AF: 0.0969

GnomAD3 exomes AF: 0.0944 AC: 23659 AN: 250620 Hom.: 1254 AF XY: 0.0956 AC XY: 12950 AN XY: 135488

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.0909

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.110

Gnomad SAS exome AF: 0.0995

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0893

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.0911 AC: 132925 AN: 1459740 Hom.: 6340 Cov.: 31 AF XY: 0.0919 AC XY: 66765 AN XY: 726190

Gnomad4 AFR exome AF: 0.0425

Gnomad4 AMR exome AF: 0.0922

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.0970

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.0871

Gnomad4 OTH exome AF: 0.0960

GnomAD4 genome AF: 0.0812 AC: 12365 AN: 152230 Hom.: 585 Cov.: 32 AF XY: 0.0827 AC XY: 6157 AN XY: 74438

Gnomad4 AFR AF: 0.0425

Gnomad4 AMR AF: 0.0856

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.0913

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0911

Gnomad4 OTH AF: 0.0955

Alfa AF: 0.0880 Hom.: 370

Bravo AF: 0.0768

Asia WGS AF: 0.119 AC: 414 AN: 3478

EpiCase AF: 0.0922

EpiControl AF: 0.0857

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	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 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 specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 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	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	-0.57
CADD	Benign	1.9
DANN	Benign	0.41

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: rs2230788; hg19: chr9-111688828; COSMIC: COSV65899026;