rs41350445

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

18

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]

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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
ELNNM_000501.4 linkuse as main transcriptc.212C>T p.Ala71Val missense_variant 5/33 ENST00000252034.12 NP_000492.2 P15502-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ELNENST00000252034.12 linkuse as main transcriptc.212C>T p.Ala71Val missense_variant 5/331 NM_000501.4 ENSP00000252034.7 P15502-2

Frequencies

GnomAD3 genomes
AF:
0.000999
AC:
152
AN:
152180
Hom.:
0
Cov.:
32
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.:
3
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.:
8
Cov.:
31
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.:
0
Cov.:
32
AF XY:
0.00111
AC XY:
83
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.:
0
Bravo
AF:
0.00105
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00164
AC:
199
Asia WGS
AF:
0.00577
AC:
20
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
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 16, 2012Ala71Val 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). -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Supravalvar aortic stenosis Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 16, 2023- -
not provided Benign:1
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Cutis laxa, autosomal dominant 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 providedclinical testingPreventionGenetics, part of Exact SciencesMay 15, 2019This 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
T
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
N
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
T
MutationAssessor
Benign
1.6
.;.;L;L;.;L;.;L;.;L;.;L;.;L;L;.;L
PrimateAI
Benign
0.46
T
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
T
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.

Other links and lift over

dbSNP: rs41350445; hg19: chr7-73455561; COSMIC: COSV52712556; COSMIC: COSV52712556; API