7-74059941-TGTGGCTCCTGGAGTTGGCTTGGCTCCTGGAGTTGGC-T

Position:

• chr7-74059941-TGTGGCTCCTGGAGTTGGCTTGGCTCCTGGAGTTGGC-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS2

The NM_000501.4(ELN):​c.1488_1523del​(p.Leu497_Gly508del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,594,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ELN NM_000501.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.13

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 Likely_benign. Variant got -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000501.4
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELN	NM_000501.4	c.1488_1523del	p.Leu497_Gly508del	inframe_deletion	23/33	ENST00000252034.12	NP_000492.2
ELN-AS1	NR_183555.1	n.127_162del		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.1488_1523del	p.Leu497_Gly508del	inframe_deletion	23/33	1	NM_000501.4	ENSP00000252034	P4
ELN-AS1	ENST00000435932.2	n.134_169del		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151358 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251462 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1442970 Hom.: 0 AF XY: 0.0000111 AC XY: 8 AN XY: 718942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000913

Gnomad4 OTH exome AF: 0.0000837

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151476 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74026

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.000476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ELN: PM4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2020	Has not been previously published as pathogenic or benign to our knowledge; In-frame deletion of 12 amino acids in a repetitive region; In silico analysis supports a deleterious effect on protein structure/function -

Supravalvar aortic stenosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 2022

This variant has not been reported in the literature in individuals affected with ELN-related conditions. This variant is present in population databases (rs782284755, gnomAD 0.02%). This variant, c.1575_1610del, results in the deletion of 12 amino acid(s) of the ELN protein (p.Leu526_Gly537del), but otherwise preserves the integrity of the reading frame. ClinVar contains an entry for this variant (Variation ID: 1313669). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782284755; hg19: chr7-73474271;