7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000501.4(ELN):c.1096+47_1096+50dupGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.030 ( 73 hom., cov: 0)

Exomes 𝑓: 0.021 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

ELN
NM_000501.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B: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: Benign. The variant received -9 ACMG points.

BP6

Variant 7-74053320-C-CTGTG is Benign according to our data. Variant chr7-74053320-C-CTGTG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360644.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0298 (4300/144206) while in subpopulation SAS AF = 0.0498 (218/4374). AF 95% confidence interval is 0.0444. There are 73 homozygotes in GnomAd4. There are 2139 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 4300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4 link	c.1096+47_1096+50dupGTGT		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+12insTGTG		intron_variant	Intron 18 of 32	1	NM_000501.4	ENSP00000252034.7		P15502-2

Frequencies

GnomAD3 genomes

AF:

0.0298

AC:

4292

AN:

144102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0346

Gnomad AMI

AF:

0.0158

Gnomad AMR

AF:

0.0237

Gnomad ASJ

AF:

0.0543

Gnomad EAS

AF:

0.0363

Gnomad SAS

AF:

0.0486

Gnomad FIN

AF:

0.0226

Gnomad MID

AF:

0.0428

Gnomad NFE

AF:

0.0267

Gnomad OTH

AF:

0.0223

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0209

AC:

29293

AN:

1401404

Hom.:

Cov.:

AF XY:

0.0215

AC XY:

14915

AN XY:

694842

show subpopulations

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

African (AFR)

AF:

0.0282

AC:

898

AN:

31806

American (AMR)

AF:

0.0139

AC:

547

AN:

39380

Ashkenazi Jewish (ASJ)

AF:

0.0370

AC:

925

AN:

24976

East Asian (EAS)

AF:

0.0218

AC:

816

AN:

37466

South Asian (SAS)

AF:

0.0378

AC:

3087

AN:

81632

European-Finnish (FIN)

AF:

0.0174

AC:

852

AN:

48972

Middle Eastern (MID)

AF:

0.0226

AC:

AN:

4198

European-Non Finnish (NFE)

AF:

0.0194

AC:

20865

AN:

1075066

Other (OTH)

AF:

0.0209

AC:

1208

AN:

57908

⚠️ 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: 0.299

Heterozygous variant carriers

2048

4096

6143

8191

10239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

812

1624

2436

3248

4060

<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:

0.0298

AC:

4300

AN:

144206

Hom.:

Cov.:

AF XY:

0.0306

AC XY:

2139

AN XY:

69924

show subpopulations

African (AFR)

AF:

0.0346

AC:

1341

AN:

38746

American (AMR)

AF:

0.0235

AC:

339

AN:

14420

Ashkenazi Jewish (ASJ)

AF:

0.0543

AC:

184

AN:

3390

East Asian (EAS)

AF:

0.0364

AC:

178

AN:

4890

South Asian (SAS)

AF:

0.0498

AC:

218

AN:

4374

European-Finnish (FIN)

AF:

0.0226

AC:

213

AN:

9432

Middle Eastern (MID)

AF:

0.0496

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0267

AC:

1755

AN:

65788

Other (OTH)

AF:

0.0220

AC:

AN:

1996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

179

359

538

718

897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0316

Hom.:

744

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Supravalvar aortic stenosis

Uncertain:1Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa, autosomal dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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