NM_000501.4:c.1741G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_000501.4(ELN):c.1741G>C(p.Gly581Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0854 in 1,614,208 control chromosomes in the GnomAD database, including 6,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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 0.062 ( 422 hom., cov: 33)

Exomes 𝑓: 0.088 ( 6308 hom. )

Consequence

ELN
NM_000501.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.24

Publications

37 publications found

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 links:

ELN-AS1 (HGNC:40212): (ELN antisense RNA 1)

ELN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 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 VariationId is 1197278.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.006361991).

BP6

Variant 7-74060495-G-C is Benign according to our data. Variant chr7-74060495-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 177898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4 link	c.1741G>C	p.Gly581Arg	missense_variant	Exon 25 of 33	ENST00000252034.12	NP_000492.2	P15502-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12 link	c.1741G>C	p.Gly581Arg	missense_variant	Exon 25 of 33	1	NM_000501.4	ENSP00000252034.7		P15502-2

Frequencies

GnomAD3 genomes

AF:

0.0621

AC:

9458

AN:

152208

Hom.:

421

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0177

Gnomad AMI

AF:

0.0921

Gnomad AMR

AF:

0.0625

Gnomad ASJ

AF:

0.0757

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0604

Gnomad FIN

AF:

0.0383

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0960

Gnomad OTH

AF:

0.0750

GnomAD2 exomes

AF:

0.0698

AC:

17545

AN:

251396

AF XY:

0.0732

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.0485

Gnomad ASJ exome

AF:

0.0714

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0486

Gnomad NFE exome

AF:

0.0991

Gnomad OTH exome

AF:

0.0851

GnomAD4 exome

AF:

0.0878

AC:

128382

AN:

1461882

Hom.:

6308

Cov.:

AF XY:

0.0877

AC XY:

63807

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0147

AC:

492

AN:

33480

American (AMR)

AF:

0.0515

AC:

2302

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0725

AC:

1894

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0659

AC:

5683

AN:

86258

European-Finnish (FIN)

AF:

0.0521

AC:

2783

AN:

53420

Middle Eastern (MID)

AF:

0.0882

AC:

508

AN:

5762

European-Non Finnish (NFE)

AF:

0.0988

AC:

109811

AN:

1112008

Other (OTH)

AF:

0.0812

AC:

4903

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

9334

18668

28001

37335

46669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3892

7784

11676

15568

19460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0621

AC:

9457

AN:

152326

Hom.:

422

Cov.:

AF XY:

0.0578

AC XY:

4307

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0177

AC:

735

AN:

41594

American (AMR)

AF:

0.0625

AC:

956

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0757

AC:

263

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5182

South Asian (SAS)

AF:

0.0609

AC:

294

AN:

4828

European-Finnish (FIN)

AF:

0.0383

AC:

407

AN:

10614

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0961

AC:

6533

AN:

68012

Other (OTH)

AF:

0.0733

AC:

155

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

453

906

1359

1812

2265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0722

Hom.:

162

Bravo

AF:

0.0613

TwinsUK

AF:

0.0982

AC:

364

ALSPAC

AF:

0.100

AC:

387

ESP6500AA

AF:

0.0197

AC:

ESP6500EA

AF:

0.0995

AC:

856

ExAC

AF:

0.0712

AC:

8638

Asia WGS

AF:

0.0290

AC:

102

AN:

3478

EpiCase

AF:

0.101

EpiControl

AF:

0.103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 02, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly581Arg in exon 25 of ELN: This variant is not expected to have clinical sig nificance because it has been identified in 9% (6470/66700) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs17855988). -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Supravalvar aortic stenosis

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa, autosomal dominant 1

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa, autosomal dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

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

0.92

LIST_S2

Benign

0.53

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0064

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;.;.;L;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

3.2

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.6

D;.;D;.;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.29

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);.;.;.;.;.;

MPC

0.22

ClinPred

0.041

GERP RS

3.5

Varity_R

0.11

gMVP

0.64

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over