7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr7-74053320-C-CTGTGTGTGTG
• rs10579871
• NM_000501.4:c.1096+41_1096+50dupGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000501.4(ELN):​c.1096+41_1096+50dupGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ELN NM_000501.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.780
• Publications: 3 publications found

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: Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• supravalvular aortic stenosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 7-74053320-C-CTGTGTGTGTG is Benign according to our data. Variant chr7-74053320-C-CTGTGTGTGTG is described in ClinVar as Likely_benign. ClinVar VariationId is 1631629.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000638 (92/144248) while in subpopulation AFR AF = 0.000955 (37/38762). AF 95% confidence interval is 0.000712. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 92 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	NM_000501.4	MANE Select	c.1096+41_1096+50dupGTGTGTGTGT		intron	N/A	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1096+41_1096+50dupGTGTGTGTGT		intron	N/A	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1096+41_1096+50dupGTGTGTGTGT		intron	N/A	NP_001265844.1	P15502-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	ENST00000252034.12	TSL:1 MANE Select	c.1096+11_1096+12insTGTGTGTGTG		intron	N/A	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1096+11_1096+12insTGTGTGTGTG		intron	N/A	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1066+11_1066+12insTGTGTGTGTG		intron	N/A	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 92 AN: 144144 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000957

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000208

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000228

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000760

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000367 AC: 520 AN: 1418058 Hom.: 0 Cov.: 0 AF XY: 0.000353 AC XY: 248 AN XY: 702794

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

African (AFR) AF: 0.000742 AC: 24 AN: 32348

American (AMR) AF: 0.000253 AC: 10 AN: 39502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25306

East Asian (EAS) AF: 0.00 AC: 0 AN: 37718

South Asian (SAS) AF: 0.000436 AC: 36 AN: 82496

European-Finnish (FIN) AF: 0.000142 AC: 7 AN: 49146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4230

European-Non Finnish (NFE) AF: 0.000388 AC: 422 AN: 1088796

Other (OTH) AF: 0.000359 AC: 21 AN: 58516

⚠️ 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.

GnomAD4 genome AF: 0.000638 AC: 92 AN: 144248 Hom.: 0 Cov.: 0 AF XY: 0.000572 AC XY: 40 AN XY: 69948

African (AFR) AF: 0.000955 AC: 37 AN: 38762

American (AMR) AF: 0.000208 AC: 3 AN: 14428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4890

South Asian (SAS) AF: 0.000229 AC: 1 AN: 4374

European-Finnish (FIN) AF: 0.000106 AC: 1 AN: 9436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000760 AC: 50 AN: 65800

Other (OTH) AF: 0.00 AC: 0 AN: 1996

Alfa AF: 0.00 Hom.: 744

Bravo AF: 0.000646

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Supravalvar aortic stenosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10579871; hg19: chr7-73467650;