rs2071307

chr7-74056384-G-Achr7-74056384-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000501.4(ELN):c.1264G>A(p.Gly422Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,613,756 control chromosomes in the GnomAD database, including 114,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G422R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (8115 hom., cov: 31)
  • Exomes 𝑓: 0.37 (106346 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.709

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.096197E-4).
• BP6: Variant 7-74056384-G-A is Benign according to our data. Variant chr7-74056384-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74056384-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.1264G>A	p.Gly422Ser	missense_variant	20/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.1264G>A	p.Gly422Ser	missense_variant	20/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46496 AN: 151764 Hom.: 8099 Cov.: 31

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.349

GnomAD3 exomes AF: 0.321 AC: 80822 AN: 251470 Hom.: 14620 AF XY: 0.324 AC XY: 44035 AN XY: 135912

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.241

Gnomad FIN exome AF: 0.354

Gnomad NFE exome AF: 0.410

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.374 AC: 547143 AN: 1461870 Hom.: 106346 Cov.: 74 AF XY: 0.371 AC XY: 269755 AN XY: 727232

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.405

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.306 AC: 46541 AN: 151886 Hom.: 8115 Cov.: 31 AF XY: 0.301 AC XY: 22341 AN XY: 74206

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.401

Gnomad4 OTH AF: 0.356

Alfa AF: 0.384 Hom.: 24904

Bravo AF: 0.297

TwinsUK AF: 0.408 AC: 1513

ALSPAC AF: 0.406 AC: 1564

ESP6500AA AF: 0.177 AC: 779

ESP6500EA AF: 0.413 AC: 3551

ExAC AF: 0.326 AC: 39602

Asia WGS AF: 0.244 AC: 847 AN: 3478

EpiCase AF: 0.406

EpiControl AF: 0.409

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2015	p.Gly422Ser in exon 20 of ELN: This variant is not expected to have clinical sig nificance because it has been identified in 42% (27817/66734) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2071307). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Supravalvar aortic stenosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Cutis laxa, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	10
Dann	Benign	0.77
DEOGEN2	Benign	0.18	T;.;T;.;.;.;.;T;.;.;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.00051	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.13	T;T;D;D;.;D;D;T;T;D;.;D;T
Sift4G	Uncertain	0.042	D;D;T;T;D;D;D;D;D;D;T;D;D
Polyphen		0.012	B;B;.;B;B;B;B;B;B;B;B;B;.
Vest4		0.13
MPC		0.18
ClinPred		0.0019	T
GERP RS		1.2
Varity_R		0.021
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2071307; hg19: chr7-73470714; COSMIC: COSV52708305; COSMIC: COSV52708305;