7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTG

Variant names:

• chr7-74053320-CTGTGTGTG-C
• rs10579871
• NM_000501.4:c.1096+43_1096+50delGTGTGTGT

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+50delGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,555,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: ELN NM_000501.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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 eas. gnomad4 allele frequency = 0.000527 (76/144210) while in subpopulation EAS AF= 0.00184 (9/4890). AF 95% confidence interval is 0.00096. There are 0 homozygotes in gnomad4. There are 34 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 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4	c.1096+43_1096+50delGTGTGTGT		intron_variant	Intron 18 of 32	ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.1096+12_1096+19delTGTGTGTG		intron_variant	Intron 18 of 32	1	NM_000501.4	ENSP00000252034.7

Frequencies

GnomAD3 genomes AF: 0.000527 AC: 76 AN: 144106 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000416

Gnomad ASJ AF: 0.000295

Gnomad EAS AF: 0.00184

Gnomad SAS AF: 0.000228

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000258

Gnomad OTH AF: 0.00101

GnomAD4 exome AF: 0.00133 AC: 1877 AN: 1411586 Hom.: 0 AF XY: 0.00146 AC XY: 1019 AN XY: 699616

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00336

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00372

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.00393

Gnomad4 NFE exome AF: 0.000977

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome AF: 0.000527 AC: 76 AN: 144210 Hom.: 0 Cov.: 0 AF XY: 0.000486 AC XY: 34 AN XY: 69926

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000416

Gnomad4 ASJ AF: 0.000295

Gnomad4 EAS AF: 0.00184

Gnomad4 SAS AF: 0.000229

Gnomad4 FIN AF: 0.000106

Gnomad4 NFE AF: 0.000258

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

Sep 21, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ELN-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the effect of this variant on mRNA splicing is currently unknown. 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. -

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;