rs41511151

chr7-74068657-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000501.4(ELN):c.2132G>A(p.Gly711Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,614,152 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (17 hom.)
• Consequence: ELN NM_000501.4 missense, splice_region
• Scores: Splicing: ADA: 0.006857
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.05

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=0.011181653).
• BP6: Variant 7-74068657-G-A is Benign according to our data. Variant chr7-74068657-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74068657-G-A is described in Lovd as [Likely_benign]. Variant chr7-74068657-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00316 (481/152288) while in subpopulation AMR AF= 0.00562 (86/15290). AF 95% confidence interval is 0.00466. There are 0 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 481 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.2132G>A	p.Gly711Asp	missense_variant, splice_region_variant	33/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.2132G>A	p.Gly711Asp	missense_variant, splice_region_variant	33/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00305 AC: 765 AN: 251040 Hom.: 2 AF XY: 0.00287 AC XY: 389 AN XY: 135718

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00436 AC: 6380 AN: 1461864 Hom.: 17 Cov.: 31 AF XY: 0.00417 AC XY: 3032 AN XY: 727240

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00519

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00527

Gnomad4 OTH exome AF: 0.00376

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74450

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00408 Hom.: 2

Bravo AF: 0.00352

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2021	This variant is associated with the following publications: (PMID: 16374472, 16081882, 19029017, 28146470) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ELN: BS1, BS2 -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 19, 2012	Gly711Asp in exon 33 of ELN: This variant is not expected to have clinical signi ficance because it has been identified in 0.4% (34/8600) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS) and in 2.5% (5/196) of Tuscan (Italian) chromosomes f rom a broad population by the 1000 Genomes project (dbSNP rs41511151). Gly711A sp in exon 33 of ELN (rs41511151; allele frequency = 0.4%, 34/8600) ** -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Supravalvar aortic stenosis Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Cutis laxa, autosomal dominant Benign:1

Likely 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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;T;.;T;T;.;.;.;.;T;.;.;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	0.96	D;D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.0	N;.;D;.;D;D;D;N;N;D;N;N;N;D;D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;.;D;.;D;D;.;D;D;D;T;D;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;.;D;D;D;D;D;D;D;D;D;D;.
Vest4		0.51
MVP		0.82
MPC		0.24
ClinPred		0.045	T
GERP RS		2.6
Varity_R		0.069
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0069
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.090		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: rs41511151; hg19: chr7-73482987;