Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000501.4(ELN):c.2033-16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,614,004 control chromosomes in the GnomAD database, including 1,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 103 hom., cov: 31)

Exomes 𝑓: 0.031 ( 933 hom. )

Consequence

ELN
NM_000501.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.670

Publications

5 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 7-74065928-A-G is Benign according to our data. Variant chr7-74065928-A-G is described in ClinVar as Benign. ClinVar VariationId is 256305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0267 (4066/152184) while in subpopulation NFE AF = 0.0361 (2455/67998). AF 95% confidence interval is 0.0349. There are 103 homozygotes in GnomAd4. There are 2002 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 4066 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000501.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ELN	NM_000501.4	MANE Select	c.2033-16A>G	intron	N/A	NP_000492.2
ELN	NM_001278939.2		c.2219-16A>G	intron	N/A	NP_001265868.1
ELN	NM_001278915.2		c.2051-16A>G	intron	N/A	NP_001265844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ELN	ENST00000252034.12	TSL:1 MANE Select	c.2033-16A>G	intron	N/A	ENSP00000252034.7
ELN	ENST00000380562.8	TSL:1	c.2051-16A>G	intron	N/A	ENSP00000369936.4
ELN	ENST00000458204.5	TSL:1	c.2003-16A>G	intron	N/A	ENSP00000403162.1

Frequencies

GnomAD3 genomes

AF:

0.0268

AC:

4068

AN:

152066

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00587

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0573

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.0785

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0361

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.0282

AC:

7082

AN:

250854

AF XY:

0.0279

show subpopulations

Gnomad AFR exome

AF:

0.00505

Gnomad AMR exome

AF:

0.00824

Gnomad ASJ exome

AF:

0.0575

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0825

Gnomad NFE exome

AF:

0.0353

Gnomad OTH exome

AF:

0.0267

GnomAD4 exome

AF:

0.0315

AC:

45986

AN:

1461820

Hom.:

933

Cov.:

AF XY:

0.0309

AC XY:

22472

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00439

AC:

147

AN:

33480

American (AMR)

AF:

0.00899

AC:

402

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0591

AC:

1545

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00716

AC:

618

AN:

86258

European-Finnish (FIN)

AF:

0.0785

AC:

4190

AN:

53378

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0336

AC:

37370

AN:

1111990

Other (OTH)

AF:

0.0279

AC:

1682

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

2528

5057

7585

10114

12642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1346

2692

4038

5384

6730

<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:

0.0267

AC:

4066

AN:

152184

Hom.:

103

Cov.:

AF XY:

0.0269

AC XY:

2002

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00583

AC:

242

AN:

41542

American (AMR)

AF:

0.0146

AC:

223

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

199

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00539

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0785

AC:

830

AN:

10574

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0361

AC:

2455

AN:

67998

Other (OTH)

AF:

0.0256

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

199

397

596

794

993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0336

Hom.:

Bravo

AF:

0.0204

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Supravalvar aortic stenosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.1

(source)

DANN

Benign

0.84

PhyloP100

-0.67

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over