rs137854454

Positions:

• chr7-74043901-C-A
• chr7-74043901-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000501.4(ELN):​c.450C>A​(p.Tyr150Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ELN NM_000501.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.260

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-74043901-C-A is Pathogenic according to our data. Variant chr7-74043901-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 265394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74043901-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.450C>A	p.Tyr150Ter	stop_gained	9/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.450C>A	p.Tyr150Ter	stop_gained	9/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2016

The Y150X pathogenic variant in the ELN gene has been reported previously in a female proband and her brother, both with mild supravalvular aortic stenosis (SVAS), as well as her son who exhibited severe SVAS, supravalvular pulmonary stenosis, and peripheral pulmonary artery stenosis (Metcalfe et al., 2000). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y150X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Y150X as a pathogenic variant. -

Supravalvar aortic stenosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

This sequence change creates a premature translational stop signal (p.Tyr150*) in the ELN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ELN are known to be pathogenic (PMID: 11175284). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with supravalvular aortic stenosis (PMID: 11175284). ClinVar contains an entry for this variant (Variation ID: 265394). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A;D
Vest4		0.86
GERP RS		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137854454; hg19: chr7-73458231;