chr7-74060495-G-C

Position:

chr7-74060495-G-C

Variant summary

Our verdict is Benign. Variant got -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 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 0.062 ( 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:9

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 links:

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

ELN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 [Likely_benign]. Clinvar id is 177898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74060495-G-C is described in Lovd as [Benign]. Variant chr7-74060495-G-C is described in Lovd as [Likely_benign].

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/exons	MANE	UniProt
ELN	NM_000501.4 linkuse as main transcript	c.1741G>C	p.Gly581Arg	missense_variant	25/33	ENST00000252034.12
ELN-AS1	NR_183555.1 linkuse as main transcript	n.72-463C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12 linkuse as main transcript	c.1741G>C	p.Gly581Arg	missense_variant	25/33	1	NM_000501.4	P4	P15502-2
ELN-AS1	ENST00000435932.2 linkuse as main transcript	n.79-463C>G		intron_variant, non_coding_transcript_variant		4

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

GnomAD3 exomes

AF:

0.0698

AC:

17545

AN:

251396

Hom.:

778

AF XY:

0.0732

AC XY:

9944

AN XY:

135882

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 SAS exome

AF:

0.0665

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

Gnomad4 AFR exome

AF:

0.0147

Gnomad4 AMR exome

AF:

0.0515

Gnomad4 ASJ exome

AF:

0.0725

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0659

Gnomad4 FIN exome

AF:

0.0521

Gnomad4 NFE exome

AF:

0.0988

Gnomad4 OTH exome

AF:

0.0812

GnomAD4 genome

AF:

0.0621

AC:

9457

AN:

152326

Hom.:

422

Cov.:

AF XY:

0.0578

AC XY:

4307

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0177

Gnomad4 AMR

AF:

0.0625

Gnomad4 ASJ

AF:

0.0757

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0609

Gnomad4 FIN

AF:

0.0383

Gnomad4 NFE

AF:

0.0961

Gnomad4 OTH

AF:

0.0733

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 02, 2015	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). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

Supravalvar aortic stenosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

- -

Cutis laxa, autosomal dominant 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cutis laxa, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

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;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.0015

P;P;P;P;P;P;P;P;P;P;P;P;P;P;P

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

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over