rs35054425

chr9-108902935-A-C

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.1758T>G(p.Pro586=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,613,206 control chromosomes in the GnomAD database, including 388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (10 hom., cov: 32)
  • Exomes 𝑓: 0.015 (378 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.437

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=-0.58).
• BP6: Variant 9-108902935-A-C is Benign according to our data. Variant chr9-108902935-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 364572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108902935-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.437 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.1758T>G	p.Pro586=	synonymous_variant	16/37	ENST00000374647.10
ELP1	NM_001318360.2	c.1416T>G	p.Pro472=	synonymous_variant	16/37
ELP1	NM_001330749.2	c.711T>G	p.Pro237=	synonymous_variant	14/35
ELP1	XM_047423991.1	c.1758T>G	p.Pro586=	synonymous_variant	16/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.1758T>G	p.Pro586=	synonymous_variant	16/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.00951 AC: 1448 AN: 152232 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0553

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.0158 AC: 3961 AN: 251174 Hom.: 87 AF XY: 0.0186 AC XY: 2522 AN XY: 135750

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00640

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0634

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0153 AC: 22339 AN: 1460856 Hom.: 378 Cov.: 30 AF XY: 0.0169 AC XY: 12282 AN XY: 726800

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00658

Gnomad4 ASJ exome AF: 0.0229

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0612

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.00950 AC: 1447 AN: 152350 Hom.: 10 Cov.: 32 AF XY: 0.00948 AC XY: 706 AN XY: 74508

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00921

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0553

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0126 Hom.: 7

Bravo AF: 0.00849

Asia WGS AF: 0.0260 AC: 90 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2017	Variant summary: The IKBKAP c.1758T>G (p.Pro586Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism 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 1977/119930 control chromosomes (50 homozygotes) at a frequency of 0.0164846, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic IKBKAP variant (0.001838), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign and another lab classified it as uncertain significance, all without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; 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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Familial dysautonomia Benign:3

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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	4.4
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35054425; hg19: chr9-111665215;