rs41350445

Positions:

chr7-74041231-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000501.4(ELN):c.212C>T(p.Ala71Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000827 in 1,613,956 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 8 hom. )

Consequence

ELN
NM_000501.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0390

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003741473).

BP6

Variant 7-74041231-C-T is Benign according to our data. Variant chr7-74041231-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74041231-C-T is described in Lovd as [Likely_benign]. Variant chr7-74041231-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000998 (152/152298) while in subpopulation EAS AF= 0.0195 (101/5178). AF 95% confidence interval is 0.0164. There are 0 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 152 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELN	NM_000501.4 linkuse as main transcript	c.212C>T	p.Ala71Val	missense_variant	5/33	ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12 linkuse as main transcript	c.212C>T	p.Ala71Val	missense_variant	5/33	1	NM_000501.4	ENSP00000252034	P4	P15502-2

Frequencies

GnomAD3 genomes

AF:

0.000999

AC:

152

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0195

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00164

AC:

412

AN:

251460

Hom.:

AF XY:

0.00161

AC XY:

219

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0183

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.000831

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000809

AC:

1182

AN:

1461658

Hom.:

Cov.:

AF XY:

0.000807

AC XY:

587

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0227

Gnomad4 SAS exome

AF:

0.000464

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000998

AC:

152

AN:

152298

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0195

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000275

Hom.:

Bravo

AF:

0.00105

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00164

AC:

199

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2012	Ala71Val in exon 5 of ELN: This variant has been reported in 2 Asian individual' s with isolated congenital ductus arteriosus aneurysm (Jan 2009). However, it is not expected to have clinical significance because it has been identified in 0. 9% (20/2222) of chromosomes from a broad, unspecified population (dbSNP rs413504 45). -

Supravalvar aortic stenosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

- -

Cutis laxa, autosomal dominant 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

ELN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

6.9

DANN

Benign

0.73

DEOGEN2

Benign

0.086

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

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.52

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

MetaRNN

Benign

0.0037

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.51

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

REVEL

Benign

0.19

Sift

Benign

0.43

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

Sift4G

Benign

0.096

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

Polyphen

0.0070

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

Vest4

0.20

MVP

0.44

MPC

0.18

ClinPred

0.0078

GERP RS

-3.3

Varity_R

0.018

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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