7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

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+45_1096+50dupGTGTGT 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 0.024 ( 59 hom., cov: 0)

Exomes 𝑓: 0.013 ( 2 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:2

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-CTGTGTG is Benign according to our data. Variant chr7-74053320-C-CTGTGTG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360645.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0238 (3427/144224) while in subpopulation AFR AF = 0.0431 (1669/38750). AF 95% confidence interval is 0.0414. There are 59 homozygotes in GnomAd4. There are 1558 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 3427 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3426

AN:

144120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0432

Gnomad AMI

AF:

0.0225

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.00619

Gnomad EAS

AF:

0.00653

Gnomad SAS

AF:

0.0119

Gnomad FIN

AF:

0.00371

Gnomad MID

AF:

0.0197

Gnomad NFE

AF:

0.0201

Gnomad OTH

AF:

0.0137

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0129

AC:

18132

AN:

1402794

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

8875

AN XY:

695822

show subpopulations

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

African (AFR)

AF:

0.0286

AC:

908

AN:

31738

American (AMR)

AF:

0.00751

AC:

296

AN:

39426

Ashkenazi Jewish (ASJ)

AF:

0.00523

AC:

132

AN:

25260

East Asian (EAS)

AF:

0.00334

AC:

126

AN:

37680

South Asian (SAS)

AF:

0.0100

AC:

823

AN:

82220

European-Finnish (FIN)

AF:

0.00364

AC:

179

AN:

49112

Middle Eastern (MID)

AF:

0.00616

AC:

AN:

4218

European-Non Finnish (NFE)

AF:

0.0139

AC:

14937

AN:

1075122

Other (OTH)

AF:

0.0122

AC:

705

AN:

58018

⚠️ 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: 0.294

Heterozygous variant carriers

1373

2746

4119

5492

6865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.0238

AC:

3427

AN:

144224

Hom.:

Cov.:

AF XY:

0.0223

AC XY:

1558

AN XY:

69936

show subpopulations

African (AFR)

AF:

0.0431

AC:

1669

AN:

38750

American (AMR)

AF:

0.0166

AC:

239

AN:

14428

Ashkenazi Jewish (ASJ)

AF:

0.00619

AC:

AN:

3392

East Asian (EAS)

AF:

0.00654

AC:

AN:

4890

South Asian (SAS)

AF:

0.0121

AC:

AN:

4374

European-Finnish (FIN)

AF:

0.00371

AC:

AN:

9434

Middle Eastern (MID)

AF:

0.0213

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0201

AC:

1325

AN:

65790

Other (OTH)

AF:

0.0135

AC:

AN:

1996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

149

298

447

596

745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0134

Hom.:

744

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Supravalvar aortic stenosis

Uncertain:1Benign:1

Jan 22, 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

- -

not provided

Benign:1

Aug 23, 2019

GeneDx

Significance:Likely benign

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