7-74059922-G-A

Position:

• chr7-74059922-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000252034.12(ELN):​c.1451G>A​(p.Gly484Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELN ENST00000252034.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.511

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELN	NM_000501.4	c.1451G>A	p.Gly484Asp	missense_variant	23/33	ENST00000252034.12	NP_000492.2
ELN-AS1	NR_183555.1	n.182C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.1451G>A	p.Gly484Asp	missense_variant	23/33	1	NM_000501.4	ENSP00000252034	P4
ELN-AS1	ENST00000435932.2	n.189C>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

May 29, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ELN protein function. This variant has not been reported in the literature in individuals affected with ELN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 513 of the ELN protein (p.Gly513Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T;T;.;D;T;.;.;.;.;T;.;.;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	.;.;.;L;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.3	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;.;D;D;D;D;.;D;D;D;D;D;.;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D;D;D;D;D;D;D;D;D;.
Vest4		0.59
MutPred		0.28		.;.;.;.;.;.;.;.;.;Gain of stability (P = 0.0697);.;.;.;.;.;
MVP		0.58
MPC		0.24
ClinPred		0.78	D
GERP RS		2.2
Varity_R		0.083
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-73474252;