rs370619098

chr7-74057387-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.1358-253G>A variant causes a intron change. The variant allele was found at a frequency of 0.00174 in 1,500,558 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: ELN NM_000501.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.71

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=0.01956901).
• BP6: Variant 7-74057387-G-A is Benign according to our data. Variant chr7-74057387-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 389824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74057387-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00135 (206/152334) while in subpopulation AMR AF= 0.00255 (39/15314). AF 95% confidence interval is 0.00191. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.1358-253G>A		intron_variant		ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.1358-253G>A		intron_variant		1	NM_000501.4	P4

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00141 AC: 216 AN: 152764 Hom.: 0 AF XY: 0.00151 AC XY: 125 AN XY: 82634

Gnomad AFR exome AF: 0.000563

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000400

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00178 AC: 2404 AN: 1348224 Hom.: 1 Cov.: 31 AF XY: 0.00176 AC XY: 1165 AN XY: 660142

Gnomad4 AFR exome AF: 0.000496

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.0000504

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00211

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74494

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000933 Hom.: 1

Bravo AF: 0.00172

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00201 AC: 8

ExAC AF: 0.00102 AC: 119

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2021	This variant is associated with the following publications: (PMID: 11735026, 15990952, 10942104) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ELN: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Supravalvar aortic stenosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.0065
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.30	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.070
Sift	Benign	0.19	T
Sift4G	Benign	0.080	T
Vest4		0.28
MVP		0.58
ClinPred		0.0097	T
GERP RS		2.9
Varity_R		0.048
gMVP		0.23

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: rs370619098; hg19: chr7-73471717;