7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr7-74053320-CTG-C
• rs10579871
• NM_000501.4:c.1096+49_1096+50delGT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000501.4(ELN):​c.1096+49_1096+50delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,549,400 control chromosomes in the GnomAD database, including 228 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.047 (221 hom., cov: 0)
  • Exomes 𝑓: 0.051 (7 hom.)
• 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-CTG-C is Benign according to our data. Variant chr7-74053320-CTG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360646.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

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+49_1096+50delGT		intron	N/A	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1096+49_1096+50delGT		intron	N/A	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1096+49_1096+50delGT		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+13delTG		intron	N/A	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1096+12_1096+13delTG		intron	N/A	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1066+12_1066+13delTG		intron	N/A	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.0472 AC: 6789 AN: 143986 Hom.: 220 Cov.: 0

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.0180

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.0304

Gnomad EAS AF: 0.0553

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0424

Gnomad MID AF: 0.0263

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0457

GnomAD4 exome AF: 0.0510 AC: 71727 AN: 1405312 Hom.: 7 AF XY: 0.0513 AC XY: 35702 AN XY: 696486

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

African (AFR) AF: 0.101 AC: 3235 AN: 32074

American (AMR) AF: 0.0498 AC: 1957 AN: 39310

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 1066 AN: 25174

East Asian (EAS) AF: 0.0930 AC: 3463 AN: 37246

South Asian (SAS) AF: 0.0644 AC: 5280 AN: 81984

European-Finnish (FIN) AF: 0.0625 AC: 3037 AN: 48626

Middle Eastern (MID) AF: 0.0521 AC: 219 AN: 4204

European-Non Finnish (NFE) AF: 0.0466 AC: 50247 AN: 1078716

Other (OTH) AF: 0.0556 AC: 3223 AN: 57978

⚠️ 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: 0.0472 AC: 6805 AN: 144088 Hom.: 221 Cov.: 0 AF XY: 0.0485 AC XY: 3390 AN XY: 69870

African (AFR) AF: 0.0883 AC: 3420 AN: 38718

American (AMR) AF: 0.0411 AC: 592 AN: 14408

Ashkenazi Jewish (ASJ) AF: 0.0304 AC: 103 AN: 3390

East Asian (EAS) AF: 0.0554 AC: 271 AN: 4890

South Asian (SAS) AF: 0.0503 AC: 220 AN: 4370

European-Finnish (FIN) AF: 0.0424 AC: 398 AN: 9396

Middle Eastern (MID) AF: 0.0248 AC: 7 AN: 282

European-Non Finnish (NFE) AF: 0.0256 AC: 1685 AN: 65754

Other (OTH) AF: 0.0467 AC: 93 AN: 1992

Alfa AF: 0.0397 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 (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10579871; hg19: chr7-73467650; COSMIC: COSV52708950; COSMIC: COSV52708950;