rs2230791

Positions:

• chr9-108901474-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003640.5(ELP1):​c.1965C>T​(p.Thr655=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.077 in 1,611,036 control chromosomes in the GnomAD database, including 5,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (846 hom., cov: 31)
  • Exomes 𝑓: 0.075 (4723 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0350

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=-0.41).
• BP6: Variant 9-108901474-G-A is Benign according to our data. Variant chr9-108901474-G-A is described in ClinVar as [Benign]. Clinvar id is 137576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108901474-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.035 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.1965C>T	p.Thr655=	synonymous_variant	18/37	ENST00000374647.10
ELP1	NM_001318360.2	c.1623C>T	p.Thr541=	synonymous_variant	18/37
ELP1	NM_001330749.2	c.918C>T	p.Thr306=	synonymous_variant	16/35
ELP1	XM_047423991.1	c.1965C>T	p.Thr655=	synonymous_variant	18/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.1965C>T	p.Thr655=	synonymous_variant	18/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 14064 AN: 152026 Hom.: 847 Cov.: 31

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0620

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0504

Gnomad FIN AF: 0.0870

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0789

Gnomad OTH AF: 0.0811

GnomAD3 exomes AF: 0.0695 AC: 17450 AN: 250976 Hom.: 760 AF XY: 0.0696 AC XY: 9437 AN XY: 135620

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0424

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0513

Gnomad FIN exome AF: 0.0838

Gnomad NFE exome AF: 0.0824

Gnomad OTH exome AF: 0.0683

GnomAD4 exome AF: 0.0754 AC: 110033 AN: 1458892 Hom.: 4723 Cov.: 32 AF XY: 0.0746 AC XY: 54162 AN XY: 725936

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.0449

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0538

Gnomad4 FIN exome AF: 0.0804

Gnomad4 NFE exome AF: 0.0801

Gnomad4 OTH exome AF: 0.0697

GnomAD4 genome AF: 0.0925 AC: 14074 AN: 152144 Hom.: 846 Cov.: 31 AF XY: 0.0911 AC XY: 6776 AN XY: 74388

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0618

Gnomad4 ASJ AF: 0.0257

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0502

Gnomad4 FIN AF: 0.0870

Gnomad4 NFE AF: 0.0790

Gnomad4 OTH AF: 0.0802

Alfa AF: 0.0825 Hom.: 524

Bravo AF: 0.0946

Asia WGS AF: 0.0290 AC: 102 AN: 3478

EpiCase AF: 0.0772

EpiControl AF: 0.0731

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, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -

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	-	- -

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	-0.41
CADD	Benign	5.7
DANN	Benign	0.57

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: rs2230791; hg19: chr9-111663754;