rs79596285

chr9-108879526-G-A

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.3492C>T(p.Asp1164=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00926 in 1,613,992 control chromosomes in the GnomAD database, including 1,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (114 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (897 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.121

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=-0.48).
• BP6: Variant 9-108879526-G-A is Benign according to our data. Variant chr9-108879526-G-A is described in ClinVar as [Benign]. Clinvar id is 364557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.121 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.3492C>T	p.Asp1164=	synonymous_variant	33/37	ENST00000374647.10
ELP1	NM_001318360.2	c.3150C>T	p.Asp1050=	synonymous_variant	33/37
ELP1	NM_001330749.2	c.2445C>T	p.Asp815=	synonymous_variant	31/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.3492C>T	p.Asp1164=	synonymous_variant	33/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2304 AN: 152140 Hom.: 112 Cov.: 33

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0885

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0447

Gnomad SAS AF: 0.00437

Gnomad FIN AF: 0.0416

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0331 AC: 8326 AN: 251308 Hom.: 706 AF XY: 0.0267 AC XY: 3627 AN XY: 135826

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0446

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.0404

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.0223

GnomAD4 exome AF: 0.00864 AC: 12636 AN: 1461734 Hom.: 897 Cov.: 31 AF XY: 0.00773 AC XY: 5623 AN XY: 727186

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.0464

Gnomad4 SAS exome AF: 0.00212

Gnomad4 FIN exome AF: 0.0364

Gnomad4 NFE exome AF: 0.000456

Gnomad4 OTH exome AF: 0.00815

GnomAD4 genome AF: 0.0152 AC: 2317 AN: 152258 Hom.: 114 Cov.: 33 AF XY: 0.0179 AC XY: 1336 AN XY: 74432

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.0892

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0448

Gnomad4 SAS AF: 0.00458

Gnomad4 FIN AF: 0.0416

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00428 Hom.: 17

Bravo AF: 0.0218

Asia WGS AF: 0.0290 AC: 101 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 25, 2016	Variant summary: The IKBKAP c.3492C>T (p.Asp1164Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3138/121288 control chromosomes (271 homozygotes) at a frequency of 0.0258723, which is approximately 14 times the estimated maximal expected allele frequency of a pathogenic IKBKAP variant (0.001838), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Familial dysautonomia Benign:2

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	5.5
Dann	Benign	0.58

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: rs79596285; hg19: chr9-111641806; COSMIC: COSV65896761;