rs61749202

Positions:

• chr9-108874950-A-C
• chr9-108874950-A-G
• chr9-108874950-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003640.5(ELP1):​c.3876T>G​(p.Thr1292=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,611,554 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 33)
  • Exomes 𝑓: 0.015 (241 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.360

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 9-108874950-A-C is Benign according to our data. Variant chr9-108874950-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 364551.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}. Variant chr9-108874950-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0128 (1952/152370) while in subpopulation AMR AF= 0.0233 (356/15300). AF 95% confidence interval is 0.0213. There are 21 homozygotes in gnomad4. There are 946 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.3876T>G	p.Thr1292=	synonymous_variant	36/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.3534T>G	p.Thr1178=	synonymous_variant	36/37		NP_001305289.1
ELP1	NM_001330749.2	c.2829T>G	p.Thr943=	synonymous_variant	34/35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.3876T>G	p.Thr1292=	synonymous_variant	36/37	1	NM_003640.5	ENSP00000363779	P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1954 AN: 152252 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00359

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0146 AC: 3677 AN: 251358 Hom.: 43 AF XY: 0.0153 AC XY: 2084 AN XY: 135860

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0542

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0147

Gnomad FIN exome AF: 0.00408

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0154 AC: 22541 AN: 1459184 Hom.: 241 Cov.: 29 AF XY: 0.0158 AC XY: 11472 AN XY: 726144

Gnomad4 AFR exome AF: 0.00332

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0508

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.00407

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0128 AC: 1952 AN: 152370 Hom.: 21 Cov.: 33 AF XY: 0.0127 AC XY: 946 AN XY: 74512

Gnomad4 AFR AF: 0.00358

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.0484

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0134 Hom.: 7

Bravo AF: 0.0138

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0195

EpiControl AF: 0.0212

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2017	Variant summary: The c.3876T>G (p.Thr1292=) in IKBKAP gene is a synonymous change that involves a non-conserved nucleotide. 4/5 programs in Alamut predict that this variant does not affect splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in control dataset of ExAC at a frequency of 0.01362 (1653/121382 chrs tested, including 21 homozygotes), predominantly in individuals of European Ancestry descent (0.01845; 1231/66722 chrs tested, including 17 homozygotes). These frequencies exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0018). The variant of interest has not, to our knowledge, been reported in affected individuals via published reports, but is cited as Benign by a reputable clinical laboratory. Taken together, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial dysautonomia Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

ELP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.4
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61749202; hg19: chr9-111637230;