chr7-74028201-C-G

Position:

• chr7-74028201-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000501.4(ELN):​c.14C>G​(p.Thr5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26872128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELN	NM_000501.4	c.14C>G	p.Thr5Arg	missense_variant	1/33	ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.14C>G	p.Thr5Arg	missense_variant	1/33	1	NM_000501.4	ENSP00000252034.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Dec 04, 2022

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 threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 5 of the ELN protein (p.Thr5Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;T;.;T;T;T;.;T;.;.;.;.;T;.;.;.;.;.;.;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.73	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.4	.;.;L;L;.;.;.;.;.;L;L;L;.;L;.;L;.;L;L;.;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N;.;N;N;N;N;N;D;N;N;N;N;N;N;N;N;N;N;N;D;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;.;D;D;D
Sift4G	Benign	0.32	T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.021	B;B;B;.;.;B;.;.;B;B;B;B;B;B;.;B;.;B;B;.;.
Vest4		0.23
MutPred		0.26		Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);Gain of methylation at T5 (P = 0.0055);
MVP		0.78
MPC		0.21
ClinPred		0.58	D
GERP RS		3.6
Varity_R		0.067
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-73442531;