NM_000501.4:c.1096+45_1096+50delGTGTGT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000501.4(ELN):c.1096+45_1096+50delGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,443,618 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 3 hom., cov: 0)

Exomes 𝑓: 0.13 ( 0 hom. )

Consequence

ELN
NM_000501.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.33

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 7-74053320-CTGTGTG-C is Benign according to our data. Variant chr7-74053320-CTGTGTG-C is described in ClinVar as Benign. ClinVar VariationId is 360647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00504 (724/143686) while in subpopulation AMR AF = 0.00828 (119/14378). AF 95% confidence interval is 0.00707. There are 3 homozygotes in GnomAd4. There are 378 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 724 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4 link	c.1096+45_1096+50delGTGTGT		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+12_1096+17delTGTGTG		intron_variant	Intron 18 of 32	1	NM_000501.4	ENSP00000252034.7		P15502-2

Frequencies

GnomAD3 genomes

AF:

0.00502

AC:

721

AN:

143600

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00828

Gnomad ASJ

AF:

0.00118

Gnomad EAS

AF:

0.00348

Gnomad SAS

AF:

0.00251

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.00667

Gnomad NFE

AF:

0.00399

Gnomad OTH

AF:

0.00254

GnomAD4 exome

AF:

0.129

AC:

167807

AN:

1299932

Hom.:

AF XY:

0.131

AC XY:

84468

AN XY:

646200

show subpopulations

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

African (AFR)

AF:

0.100

AC:

3067

AN:

30570

American (AMR)

AF:

0.181

AC:

6875

AN:

37998

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

3933

AN:

23658

East Asian (EAS)

AF:

0.152

AC:

5418

AN:

35740

South Asian (SAS)

AF:

0.142

AC:

11188

AN:

78958

European-Finnish (FIN)

AF:

0.157

AC:

7292

AN:

46552

Middle Eastern (MID)

AF:

0.143

AC:

558

AN:

3906

European-Non Finnish (NFE)

AF:

0.124

AC:

122152

AN:

988344

Other (OTH)

AF:

0.135

AC:

7324

AN:

54206

⚠️ 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: 0.275

Heterozygous variant carriers

15886

31771

47657

63542

79428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

4354

8708

13062

17416

21770

<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:

0.00504

AC:

724

AN:

143686

Hom.:

Cov.:

AF XY:

0.00543

AC XY:

378

AN XY:

69622

show subpopulations

African (AFR)

AF:

0.00491

AC:

190

AN:

38680

American (AMR)

AF:

0.00828

AC:

119

AN:

14378

Ashkenazi Jewish (ASJ)

AF:

0.00118

AC:

AN:

3388

East Asian (EAS)

AF:

0.00348

AC:

AN:

4882

South Asian (SAS)

AF:

0.00252

AC:

AN:

4362

European-Finnish (FIN)

AF:

0.0124

AC:

114

AN:

9202

Middle Eastern (MID)

AF:

0.00719

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00399

AC:

262

AN:

65642

Other (OTH)

AF:

0.00252

AC:

AN:

1988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.105

Hom.:

744

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Supravalvar aortic stenosis

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa, autosomal dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

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