rs560081099

chr7-74060429-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000501.4(ELN):c.1675G>A(p.Val559Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.135

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016669154).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000184 (28/152310) while in subpopulation SAS AF= 0.00104 (5/4828). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.1675G>A	p.Val559Ile	missense_variant	25/33	ENST00000252034.12
ELN-AS1	NR_183555.1	n.72-397C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.1675G>A	p.Val559Ile	missense_variant	25/33	1	NM_000501.4	P4
ELN-AS1	ENST00000435932.2	n.79-397C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251470 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000395 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2022

The c.1675G>A (p.V559I) alteration is located in exon 25 (coding exon 25) of the ELN gene. This alteration results from a G to A substitution at nucleotide position 1675, causing the valine (V) at amino acid position 559 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2018

- -

Supravalvar aortic stenosis;C0175702:Williams syndrome;C3276539:Cutis laxa, autosomal dominant 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Supravalvar aortic stenosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 588 of the ELN protein (p.Val588Ile). This variant is present in population databases (rs560081099, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ELN-related conditions. ClinVar contains an entry for this variant (Variation ID: 524219). 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 with a negative predictive value of 80%. 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. -

ELN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.8
Dann	Benign	0.97
DEOGEN2	Benign	0.086	T;T;.;T;T;.;.;.;.;T;.;.;.;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.017	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.29	N;.;N;.;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.73	T;.;T;.;T;T;.;T;T;T;T;T;.;T;T
Sift4G	Benign	0.18	T;T;T;T;T;D;T;T;T;T;T;T;T;T;T
Polyphen		0.019	B;B;B;.;B;B;B;B;B;B;B;B;B;B;.
Vest4		0.26
MutPred		0.27		.;.;.;.;.;.;.;.;.;Loss of disorder (P = 0.1612);.;.;.;.;.;
MVP		0.47
MPC		0.15
ClinPred		0.030	T
GERP RS		3.1
Varity_R		0.032
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs560081099; hg19: chr7-73474759;