7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_000501.4(ELN):c.1096+43_1096+50dupGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ELN
NM_000501.4 intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.780

Publications

3 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

cutis laxa, autosomal dominant 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, G2P
supravalvular aortic stenosis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
autosomal dominant cutis laxa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ELN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00284 (409/144248) while in subpopulation NFE AF = 0.00383 (252/65798). AF 95% confidence interval is 0.00344. There are 0 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4 link	c.1096+43_1096+50dupGTGTGTGT		intron_variant	Intron 18 of 32	ENST00000252034.12	NP_000492.2	P15502-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12 link	c.1096+11_1096+12insTGTGTGTG		intron_variant	Intron 18 of 32	1	NM_000501.4	ENSP00000252034.7		P15502-2

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

409

AN:

144144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00298

Gnomad AMI

AF:

0.00338

Gnomad AMR

AF:

0.000763

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00163

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000742

Gnomad MID

AF:

0.00329

Gnomad NFE

AF:

0.00383

Gnomad OTH

AF:

0.00101

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00189

AC:

2680

AN:

1416058

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

1301

AN XY:

701830

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00294

AC:

AN:

32308

American (AMR)

AF:

0.00137

AC:

AN:

39484

Ashkenazi Jewish (ASJ)

AF:

0.000356

AC:

AN:

25300

East Asian (EAS)

AF:

0.000928

AC:

AN:

37712

South Asian (SAS)

AF:

0.00154

AC:

127

AN:

82432

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

49144

Middle Eastern (MID)

AF:

0.00142

AC:

AN:

4228

European-Non Finnish (NFE)

AF:

0.00205

AC:

2228

AN:

1086986

Other (OTH)

AF:

0.00152

AC:

AN:

58464

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.296

Heterozygous variant carriers

205

410

616

821

1026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00284

AC:

409

AN:

144248

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

173

AN XY:

69950

show subpopulations

African (AFR)

AF:

0.00297

AC:

115

AN:

38764

American (AMR)

AF:

0.000762

AC:

AN:

14428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3392

East Asian (EAS)

AF:

0.00164

AC:

AN:

4890

South Asian (SAS)

AF:

0.00229

AC:

AN:

4374

European-Finnish (FIN)

AF:

0.000742

AC:

AN:

9436

Middle Eastern (MID)

AF:

0.00355

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00383

AC:

252

AN:

65798

Other (OTH)

AF:

0.00100

AC:

AN:

1996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00136

Hom.:

744

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Supravalvar aortic stenosis

Uncertain:1

Jul 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the effect of this variant on mRNA splicing is currently unknown. This variant has not been reported in the literature in individuals affected with ELN-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 18 of the ELN gene. It does not directly change the encoded amino acid sequence of the ELN protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.78

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over