rs34852121
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000501.4(ELN):c.1951G>A(p.Gly651Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000589 in 1,613,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
ELN
NM_000501.4 missense
NM_000501.4 missense
Scores
3
6
9
Clinical Significance
Conservation
PhyloP100: 4.81
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 Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ELN | NM_000501.4 | c.1951G>A | p.Gly651Arg | missense_variant | 29/33 | ENST00000252034.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ELN | ENST00000252034.12 | c.1951G>A | p.Gly651Arg | missense_variant | 29/33 | 1 | NM_000501.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251484Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135920
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GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461518Hom.: 0 Cov.: 33 AF XY: 0.0000646 AC XY: 47AN XY: 727074
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 24, 2015 | The p.Gly651Arg variant in ELN has not been previously reported in individuals w ith pulmonary disease, but has been identified in 4/66714 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs34852121). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Gly651Arg variant is uncertain. - |
Supravalvar aortic stenosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 03, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 228664). This variant has not been reported in the literature in individuals affected with ELN-related conditions. This variant is present in population databases (rs34852121, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 713 of the ELN protein (p.Gly713Arg). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
DEOGEN2
Benign
T;T;.;T;T;.;.;.;.;T;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
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;.;D;.;D;D;D;N;N;D;N;N;N;D;D
REVEL
Uncertain
Sift
Pathogenic
D;.;D;.;D;D;.;D;D;D;D;D;.;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
D;D;D;.;D;D;D;D;D;D;D;D;D;D;.
Vest4
MutPred
0.31
.;.;.;.;.;.;.;.;.;Gain of methylation at G641 (P = 0.0046);.;.;.;.;.;
MVP
MPC
0.22
ClinPred
T
GERP RS
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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