7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTG

Variant names:

• chr7-74053320-CTGTGTG-C
• rs10579871
• NM_000501.4:c.1096+45_1096+50delGTGTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.33
• 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 -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.

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+45_1096+50delGTGTGT		intron	N/A	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1096+45_1096+50delGTGTGT		intron	N/A	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1096+45_1096+50delGTGTGT		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+12_1096+17delTGTGTG		intron	N/A	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1096+12_1096+17delTGTGTG		intron	N/A	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1066+12_1066+17delTGTGTG		intron	N/A	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 721 AN: 143600 Hom.: 3 Cov.: 0

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.: 0 AF XY: 0.131 AC XY: 84468 AN XY: 646200

⚠️ 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.

GnomAD4 genome AF: 0.00504 AC: 724 AN: 143686 Hom.: 3 Cov.: 0 AF XY: 0.00543 AC XY: 378 AN XY: 69622

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: 4 AN: 3388

East Asian (EAS) AF: 0.00348 AC: 17 AN: 4882

South Asian (SAS) AF: 0.00252 AC: 11 AN: 4362

European-Finnish (FIN) AF: 0.0124 AC: 114 AN: 9202

Middle Eastern (MID) AF: 0.00719 AC: 2 AN: 278

European-Non Finnish (NFE) AF: 0.00399 AC: 262 AN: 65642

Other (OTH) AF: 0.00252 AC: 5 AN: 1988

Alfa AF: 0.105 Hom.: 744

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Supravalvar aortic stenosis (2)
-	-	1	Cutis laxa, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
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;