rs61734584

chr7-74060037-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000501.4(ELN):c.1566T>A(p.Gly522=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,614,022 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (16 hom.)
• Consequence: ELN NM_000501.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.68

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-74060037-T-A is Benign according to our data. Variant chr7-74060037-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 213164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74060037-T-A is described in Lovd as [Benign]. Variant chr7-74060037-T-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00294 (447/152138) while in subpopulation AMR AF= 0.00634 (97/15294). AF 95% confidence interval is 0.00532. There are 2 homozygotes in gnomad4. There are 217 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 451 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.1566T>A	p.Gly522=	synonymous_variant	23/33	ENST00000252034.12
ELN-AS1	NR_183555.1	n.72-5A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.1566T>A	p.Gly522=	synonymous_variant	23/33	1	NM_000501.4	P4
ELN-AS1	ENST00000435932.2	n.79-5A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 451 AN: 152020 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00350 AC: 879 AN: 251430 Hom.: 5 AF XY: 0.00366 AC XY: 498 AN XY: 135908

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.0252

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00275 AC: 4015 AN: 1461884 Hom.: 16 Cov.: 31 AF XY: 0.00289 AC XY: 2099 AN XY: 727244

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.0249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00531

GnomAD4 genome AF: 0.00294 AC: 447 AN: 152138 Hom.: 2 Cov.: 32 AF XY: 0.00292 AC XY: 217 AN XY: 74374

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00533 Hom.: 2

Bravo AF: 0.00352

EpiCase AF: 0.00496

EpiControl AF: 0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 13, 2016	p.Gly528Gly in exon 23 of ELN: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.4% (283/66738) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNPrs61734584). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ELN: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Supravalvar aortic stenosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Cutis laxa, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

ELN-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 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
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.71
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs61734584; hg19: chr7-73474367; COSMIC: COSV52711151; COSMIC: COSV52711151;