7-74053320-CTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Position:

• chr7-74053320-CTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000501.4(ELN):​c.1096+43_1096+50dup variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ELN NM_000501.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.780

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00284 (409/144248) while in subpopulation NFE AF= 0.00383 (252/65798). AF 95% confidence interval is 0.00344. There are 0 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.1096+43_1096+50dup		intron_variant		ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.1096+43_1096+50dup		intron_variant		1	NM_000501.4	P4

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 409 AN: 144144 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00298

Gnomad AMI AF: 0.00338

Gnomad AMR AF: 0.000763

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00163

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000742

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.00383

Gnomad OTH AF: 0.00101

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00189 AC: 2680 AN: 1416058 Hom.: 0 Cov.: 0 AF XY: 0.00185 AC XY: 1301 AN XY: 701830

Gnomad4 AFR exome AF: 0.00294

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.000356

Gnomad4 EAS exome AF: 0.000928

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.000753

Gnomad4 NFE exome AF: 0.00205

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00284 AC: 409 AN: 144248 Hom.: 0 Cov.: 0 AF XY: 0.00247 AC XY: 173 AN XY: 69950

Gnomad4 AFR AF: 0.00297

Gnomad4 AMR AF: 0.000762

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00164

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.000742

Gnomad4 NFE AF: 0.00383

Gnomad4 OTH AF: 0.00100

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Supravalvar aortic stenosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 24, 2021

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 effect of this variant on mRNA splicing is currently unknown. This variant has not been reported in the literature in individuals affected with ELN-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 18 of the ELN gene. It does not directly change the encoded amino acid sequence of the ELN protein. -

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: rs10579871; hg19: chr7-73467650;