rs782285456
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000501.4(ELN):c.767C>T(p.Ala256Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,890 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
ELN
NM_000501.4 missense
NM_000501.4 missense
Scores
5
13
Clinical Significance
Conservation
PhyloP100: 0.539
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=0.08888665).
BP6
?
Variant 7-74048524-C-T is Benign according to our data. Variant chr7-74048524-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572254.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS2
?
High AC in GnomAdExome at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ELN | NM_000501.4 | c.767C>T | p.Ala256Val | missense_variant | 15/33 | ENST00000252034.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ELN | ENST00000252034.12 | c.767C>T | p.Ala256Val | missense_variant | 15/33 | 1 | NM_000501.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152098Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000442 AC: 11AN: 249016Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 134798
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461792Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727210
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152098Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74296
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Supravalvar aortic stenosis Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 28, 2018 | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: Not Available; Align-GVGD: "Class C0"). This sequence change replaces alanine with valine at codon 256 of the ELN protein (p.Ala256Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs782285456, ExAC 0.03%). This variant has not been reported in the literature in individuals with ELN-related disease. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 19, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cutis laxa, autosomal dominant 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 19, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;.;T;T;.;T;.;.;.;.;T;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
Sift
Uncertain
D;.;D;D;D;D;D;D;.;D;D;D;D;D;.;D;D
Sift4G
Uncertain
D;D;D;T;T;D;T;D;D;D;T;D;D;D;D;D;D
Polyphen
B;B;B;.;B;.;.;B;B;B;B;B;B;B;B;B;.
Vest4
MutPred
0.29
.;.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0795);.;Gain of MoRF binding (P = 0.0795);.;.;.;.;.;
MVP
MPC
0.18
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