7-74059940-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000252034.12(ELN):ā€‹c.1469G>Cā€‹(p.Gly490Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G490S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000028 ( 0 hom. )

Consequence

ELN
ENST00000252034.12 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.41
Variant links:
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]
ELN-AS1 (HGNC:40212): (ELN antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ELNNM_000501.4 linkuse as main transcriptc.1469G>C p.Gly490Ala missense_variant 23/33 ENST00000252034.12 NP_000492.2
ELN-AS1NR_183555.1 linkuse as main transcriptn.164C>G non_coding_transcript_exon_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ELNENST00000252034.12 linkuse as main transcriptc.1469G>C p.Gly490Ala missense_variant 23/331 NM_000501.4 ENSP00000252034 P4P15502-2
ELN-AS1ENST00000435932.2 linkuse as main transcriptn.171C>G non_coding_transcript_exon_variant 2/24

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251480
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1452394
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
723172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000362
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000935
Hom.:
0
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Supravalvar aortic stenosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 11, 2022In 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. 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: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1001627). This variant has not been reported in the literature in individuals affected with ELN-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 519 of the ELN protein (p.Gly519Ala). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Uncertain
0.012
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
17
DANN
Benign
0.94
DEOGEN2
Benign
0.35
T;T;.;D;T;.;.;.;.;T;.;.;.;.;.
Eigen
Benign
-0.052
Eigen_PC
Benign
-0.23
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.80
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.033
D
MetaRNN
Uncertain
0.69
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
.;.;.;L;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
0.94
D;D;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-3.7
D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Benign
0.28
Sift
Pathogenic
0.0
D;.;D;D;D;D;.;D;D;D;D;D;.;D;D
Sift4G
Benign
0.27
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
1.0
D;D;D;.;D;D;D;D;D;D;D;D;D;D;.
Vest4
0.64
MutPred
0.22
.;.;.;.;.;.;.;.;.;Gain of stability (P = 0.0697);.;.;.;.;.;
MVP
0.60
MPC
0.20
ClinPred
0.45
T
GERP RS
2.3
Varity_R
0.061
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554682884; hg19: chr7-73474270; API