rs185060213
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000501.4(ELN):c.1358-192C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000345 in 1,538,164 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000085 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
ELN
NM_000501.4 intron
NM_000501.4 intron
Scores
2
4
12
Clinical Significance
Conservation
PhyloP100: 1.68
Genes affected
ELN (HGNC:3327): (elastin) This gene encodes a protein that is one of the two components of elastic fibers. Elastic fibers comprise part of the extracellular matrix and confer elasticity to organs and tissues including the heart, skin, lungs, ligaments, and blood vessels. The encoded protein is rich in hydrophobic amino acids such as glycine and proline, which form mobile hydrophobic regions bounded by crosslinks between lysine residues. Degradation products of the encoded protein, known as elastin-derived peptides or elastokines, bind the elastin receptor complex and other receptors and stimulate migration and proliferation of monocytes and skin fibroblasts. Elastokines can also contribute to cancer progression. Deletions and mutations in this gene are associated with supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.101555824).
BP6
?
Variant 7-74057448-C-T is Benign according to our data. Variant chr7-74057448-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 524221.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
BS2
?
High AC in GnomAd4 at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ELN | NM_000501.4 | c.1358-192C>T | intron_variant | ENST00000252034.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ELN | ENST00000252034.12 | c.1358-192C>T | intron_variant | 1 | NM_000501.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152042Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000109 AC: 2AN: 183466Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 99194
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GnomAD4 exome AF: 0.0000289 AC: 40AN: 1386004Hom.: 0 Cov.: 31 AF XY: 0.0000338 AC XY: 23AN XY: 681080
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GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152160Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74408
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Supravalvar aortic stenosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 475 of the ELN protein (p.Pro475Leu). This variant is present in population databases (rs185060213, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of ELN-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 524221). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ELN protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
See cases Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 21, 2022 | ACMG classification criteria: BS1, BS2, BP4 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Benign
T
Vest4
MVP
ClinPred
T
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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