NM_000501.4:c.1096+49_1096+50dupGT

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_000501.4(ELN):c.1096+49_1096+50dupGT 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 0.13 ( 1264 hom., cov: 0)

Exomes 𝑓: 0.11 ( 4 hom. )

Consequence

ELN
NM_000501.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B: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-CTG is Benign according to our data. Variant chr7-74053320-C-CTG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360643.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4 link	c.1096+49_1096+50dupGT		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+12insTG		intron_variant	Intron 18 of 32	1	NM_000501.4	ENSP00000252034.7		P15502-2

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

19364

AN:

144016

Hom.:

1263

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.168

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.0945

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.197

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.146

GnomAD4 exome

AF:

0.113

AC:

154927

AN:

1376902

Hom.:

Cov.:

AF XY:

0.112

AC XY:

76710

AN XY:

682936

show subpopulations

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

African (AFR)

AF:

0.0989

AC:

3126

AN:

31600

American (AMR)

AF:

0.0798

AC:

3116

AN:

39024

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

3133

AN:

24596

East Asian (EAS)

AF:

0.0588

AC:

2192

AN:

37276

South Asian (SAS)

AF:

0.103

AC:

8359

AN:

80804

European-Finnish (FIN)

AF:

0.0845

AC:

4112

AN:

48658

Middle Eastern (MID)

AF:

0.141

AC:

575

AN:

4092

European-Non Finnish (NFE)

AF:

0.117

AC:

123688

AN:

1053922

Other (OTH)

AF:

0.116

AC:

6626

AN:

56930

⚠️ 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: 0.328

Heterozygous variant carriers

9874

19748

29621

39495

49369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4756

9512

14268

19024

23780

<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:

0.134

AC:

19374

AN:

144118

Hom.:

1264

Cov.:

AF XY:

0.131

AC XY:

9130

AN XY:

69874

show subpopulations

African (AFR)

AF:

0.122

AC:

4725

AN:

38714

American (AMR)

AF:

0.113

AC:

1629

AN:

14418

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

577

AN:

3390

East Asian (EAS)

AF:

0.0939

AC:

459

AN:

4888

South Asian (SAS)

AF:

0.133

AC:

581

AN:

4370

European-Finnish (FIN)

AF:

0.101

AC:

954

AN:

9416

Middle Eastern (MID)

AF:

0.206

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.151

AC:

9956

AN:

65760

Other (OTH)

AF:

0.144

AC:

286

AN:

1992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

755

1510

2264

3019

3774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<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:

0.137

Hom.:

744

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Supravalvar aortic stenosis

Uncertain:2Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa, autosomal dominant

Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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

- -

not provided

Benign:1

Aug 26, 2019

GeneDx

Significance: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 (auto)

(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