rs10979605

Positions:

• chr9-108901513-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.1926G>A​(p.Thr642=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0785 in 1,610,884 control chromosomes in the GnomAD database, including 5,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (856 hom., cov: 31)
  • Exomes 𝑓: 0.077 (4889 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.14

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=-0.55).
• BP6: Variant 9-108901513-C-T is Benign according to our data. Variant chr9-108901513-C-T is described in ClinVar as [Benign]. Clinvar id is 137575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108901513-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.1926G>A	p.Thr642=	synonymous_variant	18/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.1584G>A	p.Thr528=	synonymous_variant	18/37		NP_001305289.1
ELP1	NM_001330749.2	c.879G>A	p.Thr293=	synonymous_variant	16/35		NP_001317678.1
ELP1	XM_047423991.1	c.1926G>A	p.Thr642=	synonymous_variant	18/25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.1926G>A	p.Thr642=	synonymous_variant	18/37	1	NM_003640.5	ENSP00000363779	P1

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 14189 AN: 152022 Hom.: 860 Cov.: 31

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0612

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0510

Gnomad FIN AF: 0.0975

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0808

Gnomad OTH AF: 0.0823

GnomAD3 exomes AF: 0.0715 AC: 17953 AN: 251124 Hom.: 798 AF XY: 0.0714 AC XY: 9692 AN XY: 135682

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0424

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0514

Gnomad FIN exome AF: 0.0925

Gnomad NFE exome AF: 0.0849

Gnomad OTH exome AF: 0.0694

GnomAD4 exome AF: 0.0769 AC: 112226 AN: 1458744 Hom.: 4889 Cov.: 32 AF XY: 0.0760 AC XY: 55200 AN XY: 725844

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.0447

Gnomad4 ASJ exome AF: 0.0292

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0537

Gnomad4 FIN exome AF: 0.0888

Gnomad4 NFE exome AF: 0.0817

Gnomad4 OTH exome AF: 0.0707

GnomAD4 genome AF: 0.0933 AC: 14201 AN: 152140 Hom.: 856 Cov.: 31 AF XY: 0.0924 AC XY: 6873 AN XY: 74360

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0610

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0508

Gnomad4 FIN AF: 0.0975

Gnomad4 NFE AF: 0.0808

Gnomad4 OTH AF: 0.0814

Alfa AF: 0.0824 Hom.: 855

Bravo AF: 0.0945

Asia WGS AF: 0.0300 AC: 103 AN: 3478

EpiCase AF: 0.0791

EpiControl AF: 0.0749

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	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. -

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	-0.55
CADD	Benign	0.95
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10979605; hg19: chr9-111663793;