rs1140064
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_003640.5(ELP1):c.934G>A(p.Glu312Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0221 in 1,613,956 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.021 ( 43 hom., cov: 33)
Exomes 𝑓: 0.022 ( 435 hom. )
Consequence
ELP1
NM_003640.5 missense
NM_003640.5 missense
Scores
2
16
Clinical Significance
Conservation
PhyloP100: 3.65
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0025151968).
BP6
Variant 9-108916228-C-T is Benign according to our data. Variant chr9-108916228-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108916228-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0211 (3212/152316) while in subpopulation NFE AF= 0.0247 (1678/68028). AF 95% confidence interval is 0.0237. There are 43 homozygotes in gnomad4. There are 1576 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 43 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ELP1 | NM_003640.5 | c.934G>A | p.Glu312Lys | missense_variant | 10/37 | ENST00000374647.10 | NP_003631.2 | |
ELP1 | NM_001318360.2 | c.592G>A | p.Glu198Lys | missense_variant | 10/37 | NP_001305289.1 | ||
ELP1 | XM_047423991.1 | c.934G>A | p.Glu312Lys | missense_variant | 10/25 | XP_047279947.1 | ||
ELP1 | NM_001330749.2 | c.-114G>A | 5_prime_UTR_variant | 8/35 | NP_001317678.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ELP1 | ENST00000374647.10 | c.934G>A | p.Glu312Lys | missense_variant | 10/37 | 1 | NM_003640.5 | ENSP00000363779.5 |
Frequencies
GnomAD3 genomes AF: 0.0210 AC: 3200AN: 152198Hom.: 42 Cov.: 33
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GnomAD3 exomes AF: 0.0189 AC: 4765AN: 251452Hom.: 72 AF XY: 0.0192 AC XY: 2603AN XY: 135888
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GnomAD4 exome AF: 0.0223 AC: 32522AN: 1461640Hom.: 435 Cov.: 31 AF XY: 0.0215 AC XY: 15645AN XY: 727138
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GnomAD4 genome AF: 0.0211 AC: 3212AN: 152316Hom.: 43 Cov.: 33 AF XY: 0.0212 AC XY: 1576AN XY: 74474
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ESP6500AA
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial dysautonomia Benign:4
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 09, 2014 | - - |
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. | Apr 14, 2020 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 28, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at