rs148378319
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_003640.5(ELP1):c.1886G>A(p.Arg629His) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,614,090 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R629C) has been classified as Uncertain significance.
Frequency
Consequence
NM_003640.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ELP1 | NM_003640.5 | c.1886G>A | p.Arg629His | missense_variant | 17/37 | ENST00000374647.10 | |
ELP1 | NM_001318360.2 | c.1544G>A | p.Arg515His | missense_variant | 17/37 | ||
ELP1 | NM_001330749.2 | c.839G>A | p.Arg280His | missense_variant | 15/35 | ||
ELP1 | XM_047423991.1 | c.1886G>A | p.Arg629His | missense_variant | 17/25 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ELP1 | ENST00000374647.10 | c.1886G>A | p.Arg629His | missense_variant | 17/37 | 1 | NM_003640.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00202 AC: 308AN: 152188Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00194 AC: 488AN: 251240Hom.: 0 AF XY: 0.00193 AC XY: 262AN XY: 135766
GnomAD4 exome AF: 0.00273 AC: 3993AN: 1461784Hom.: 12 Cov.: 32 AF XY: 0.00279 AC XY: 2029AN XY: 727198
GnomAD4 genome AF: 0.00202 AC: 308AN: 152306Hom.: 1 Cov.: 32 AF XY: 0.00192 AC XY: 143AN XY: 74492
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 27, 2021 | This variant is associated with the following publications: (PMID: 27582484) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | ELP1: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 09, 2017 | - - |
Familial dysautonomia Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 21, 2021 | The ELP1 c.1886G>A; p.Arg629His variant (rs148378319), is reported in the literature in a cohort of Paclitaxel-induced peripheral neuropathy, but has been found in association with familial dysautonomia with no second variant detected (Apellaniz-Ruiz 2017). This variant is reported as uncertain significance or likely benign in ClinVar (Variation ID: 194739), and is found in the general population with an overall allele frequency of 0.019% (550/282,634 alleles) in the Genome Aggregation Database. The arginine at codon 629 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg629His variant is uncertain at this time. References: Apellaniz-Ruiz et al. Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy. Clin Cancer Res. 2017 Mar 1;23(5):1227-1235. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 14, 2020 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 19, 2018 | Variant summary: IKBKAP c.1886G>A (p.Arg629His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 276958 control chromosomes. The observed variant frequency is slightly above the estimated maximal expected allele frequency for a pathogenic variant in IKBKAP causing Familial Dysautonomia phenotype (0.0018), suggesting that the variant may be benign. c.1886G>A has been reported in the literature in individuals affected with glioma and induced peripheral neuropathy, but not familial dysautonomia. Therefore, these reports do not provide unequivocal conclusions about an association of the variant with familial dysautonomia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with two classifying the variant as uncertain significance and one classifying at likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at