rs6979788

chr7-74051955-A-G

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.921A>G(p.Ala307=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,612,068 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: ELN NM_000501.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -6.54

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-74051955-A-G is Benign according to our data. Variant chr7-74051955-A-G is described in ClinVar as [Benign]. Clinvar id is 360640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74051955-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00301 (458/152312) while in subpopulation AFR AF= 0.0106 (441/41578). AF 95% confidence interval is 0.00979. There are 6 homozygotes in gnomad4. There are 217 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 458 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.921A>G	p.Ala307=	synonymous_variant	17/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.921A>G	p.Ala307=	synonymous_variant	17/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 458 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000883 AC: 216 AN: 244534 Hom.: 2 AF XY: 0.000680 AC XY: 91 AN XY: 133888

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000727

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.000375 AC: 547 AN: 1459756 Hom.: 1 Cov.: 31 AF XY: 0.000333 AC XY: 242 AN XY: 726186

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.000930

GnomAD4 genome AF: 0.00301 AC: 458 AN: 152312 Hom.: 6 Cov.: 32 AF XY: 0.00291 AC XY: 217 AN XY: 74474

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000833 Hom.: 0

Bravo AF: 0.00336

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Supravalvar aortic stenosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 20, 2021

- -

Cutis laxa, autosomal dominant 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.060
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6979788; hg19: chr7-73466285;