rs17855988

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4BP6BS2

The NM_000501.4(ELN):​c.1741G>A​(p.Gly581Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,094 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G581E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ELN
NM_000501.4 missense

Scores

2
7
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.24
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 Likely_benign. Variant got -4 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-74060495-GG-CA is described in ClinVar as [Pathogenic]. Clinvar id is 1197278.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.3348994).
BP6
Variant 7-74060495-G-A is Benign according to our data. Variant chr7-74060495-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2074756.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ELNNM_000501.4 linkuse as main transcriptc.1741G>A p.Gly581Arg missense_variant 25/33 ENST00000252034.12
ELN-AS1NR_183555.1 linkuse as main transcriptn.72-463C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ELNENST00000252034.12 linkuse as main transcriptc.1741G>A p.Gly581Arg missense_variant 25/331 NM_000501.4 P4P15502-2
ELN-AS1ENST00000435932.2 linkuse as main transcriptn.79-463C>T intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251396
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135882
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 02, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25388916, 23401415) -
Supravalvar aortic stenosis Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJun 06, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.34
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;T;.;D;T;.;.;.;.;T;.;.;.;.;.
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.53
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.067
D
MetaRNN
Benign
0.33
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
1.8
.;.;.;L;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-4.6
D;.;D;.;D;D;D;D;D;D;D;D;D;D;D
REVEL
Benign
0.25
Sift
Pathogenic
0.0
D;.;D;.;D;D;.;D;D;D;D;D;.;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;.;D;D;D;D;D;D;D;D;D;D;.
Vest4
0.90
MutPred
0.40
.;.;.;.;.;.;.;.;.;Gain of methylation at G571 (P = 0.0126);.;.;.;.;.;
MVP
0.76
MPC
0.22
ClinPred
0.97
D
GERP RS
3.5
Varity_R
0.11
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs17855988; hg19: chr7-73474825; API