7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• 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 -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.

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+50dupGTGTGT		intron	N/A	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1096+45_1096+50dupGTGTGT		intron	N/A	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1096+45_1096+50dupGTGTGT		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+12insTGTGTG		intron	N/A	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1096+11_1096+12insTGTGTG		intron	N/A	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1066+11_1066+12insTGTGTG		intron	N/A	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3426 AN: 144120 Hom.: 59 Cov.: 0

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.: 2 Cov.: 0 AF XY: 0.0128 AC XY: 8875 AN XY: 695822

⚠️ 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: 26 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.

GnomAD4 genome AF: 0.0238 AC: 3427 AN: 144224 Hom.: 59 Cov.: 0 AF XY: 0.0223 AC XY: 1558 AN XY: 69936

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: 21 AN: 3392

East Asian (EAS) AF: 0.00654 AC: 32 AN: 4890

South Asian (SAS) AF: 0.0121 AC: 53 AN: 4374

European-Finnish (FIN) AF: 0.00371 AC: 35 AN: 9434

Middle Eastern (MID) AF: 0.0213 AC: 6 AN: 282

European-Non Finnish (NFE) AF: 0.0201 AC: 1325 AN: 65790

Other (OTH) AF: 0.0135 AC: 27 AN: 1996

Alfa AF: 0.0134 Hom.: 744

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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