NM_000501.4:c.1264G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000501.4(ELN):c.1264G>A(p.Gly422Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,613,756 control chromosomes in the GnomAD database, including 114,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. G422R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.31 ( 8115 hom., cov: 31)

Exomes 𝑓: 0.37 ( 106346 hom. )

Consequence

ELN
NM_000501.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.709

Publications

77 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 Gene-Disease associations (from GenCC):

cutis laxa, autosomal dominant 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, G2P
supravalvular aortic stenosis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
autosomal dominant cutis laxa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ELN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.096197E-4).

BP6

Variant 7-74056384-G-A is Benign according to our data. Variant chr7-74056384-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4 link	c.1264G>A	p.Gly422Ser	missense_variant	Exon 20 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.1264G>A	p.Gly422Ser	missense_variant	Exon 20 of 33	1	NM_000501.4	ENSP00000252034.7		P15502-2

Frequencies

GnomAD3 genomes

AF:

0.306

AC:

46496

AN:

151764

Hom.:

8099

Cov.:

show subpopulations

Gnomad AFR

AF:

0.165

Gnomad AMI

AF:

0.445

Gnomad AMR

AF:

0.276

Gnomad ASJ

AF:

0.463

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.401

Gnomad OTH

AF:

0.349

GnomAD2 exomes

AF:

0.321

AC:

80822

AN:

251470

AF XY:

0.324

show subpopulations

Gnomad AFR exome

AF:

0.164

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.459

Gnomad EAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.354

Gnomad NFE exome

AF:

0.410

Gnomad OTH exome

AF:

0.372

GnomAD4 exome

AF:

0.374

AC:

547143

AN:

1461870

Hom.:

106346

Cov.:

AF XY:

0.371

AC XY:

269755

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.156

AC:

5233

AN:

33478

American (AMR)

AF:

0.227

AC:

10143

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

12051

AN:

26136

East Asian (EAS)

AF:

0.155

AC:

6149

AN:

39700

South Asian (SAS)

AF:

0.237

AC:

20476

AN:

86256

European-Finnish (FIN)

AF:

0.357

AC:

19074

AN:

53420

Middle Eastern (MID)

AF:

0.379

AC:

2187

AN:

5764

European-Non Finnish (NFE)

AF:

0.405

AC:

450259

AN:

1111998

Other (OTH)

AF:

0.357

AC:

21571

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

23732

47464

71197

94929

118661

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13598

27196

40794

54392

67990

<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:

0.306

AC:

46541

AN:

151886

Hom.:

8115

Cov.:

AF XY:

0.301

AC XY:

22341

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.165

AC:

6862

AN:

41474

American (AMR)

AF:

0.276

AC:

4210

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.463

AC:

1605

AN:

3468

East Asian (EAS)

AF:

0.124

AC:

640

AN:

5156

South Asian (SAS)

AF:

0.226

AC:

1088

AN:

4810

European-Finnish (FIN)

AF:

0.345

AC:

3637

AN:

10538

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.401

AC:

27224

AN:

67878

Other (OTH)

AF:

0.356

AC:

752

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1535

3070

4604

6139

7674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.375

Hom.:

47317

Bravo

AF:

0.297

TwinsUK

AF:

0.408

AC:

1513

ALSPAC

AF:

0.406

AC:

1564

ESP6500AA

AF:

0.177

AC:

779

ESP6500EA

AF:

0.413

AC:

3551

ExAC

AF:

0.326

AC:

39602

Asia WGS

AF:

0.244

AC:

847

AN:

3478

EpiCase

AF:

0.406

EpiControl

AF:

0.409

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly422Ser in exon 20 of ELN: This variant is not expected to have clinical sig nificance because it has been identified in 42% (27817/66734) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2071307). -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Jun 06, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign

0.17

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.18

T;.;T;.;.;.;.;T;.;.;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.38

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

MetaRNN

Benign

0.00051

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

.;N;N;.;N;.;.;.;.;.;.;N;N

PhyloP100

0.71

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.038

Sift

Benign

0.13

T;T;D;D;.;D;D;T;T;D;.;D;T

Sift4G

Uncertain

0.042

D;D;T;T;D;D;D;D;D;D;T;D;D

Polyphen

0.012

B;B;.;B;B;B;B;B;B;B;B;B;.

Vest4

0.13

MPC

0.18

ClinPred

0.0019

GERP RS

1.2

Varity_R

0.021

gMVP

0.57

Mutation Taster

=98/2

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