7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr7-74053320-C-CTGTG
• rs10579871
• NM_000501.4:c.1096+47_1096+50dupGTGT

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+47_1096+50dupGTGT 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 0.030 (73 hom., cov: 0)
  • Exomes 𝑓: 0.021 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ELN NM_000501.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• supravalvular aortic stenosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 7-74053320-C-CTGTG is Benign according to our data. Variant chr7-74053320-C-CTGTG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360644.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0298 (4300/144206) while in subpopulation SAS AF = 0.0498 (218/4374). AF 95% confidence interval is 0.0444. There are 73 homozygotes in GnomAd4. There are 2139 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4300 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+47_1096+50dupGTGT		intron	N/A	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1096+47_1096+50dupGTGT		intron	N/A	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1096+47_1096+50dupGTGT		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+12insTGTG		intron	N/A	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1096+11_1096+12insTGTG		intron	N/A	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1066+11_1066+12insTGTG		intron	N/A	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4292 AN: 144102 Hom.: 72 Cov.: 0

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.0158

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0543

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.0486

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.0428

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0223

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0209 AC: 29293 AN: 1401404 Hom.: 1 Cov.: 0 AF XY: 0.0215 AC XY: 14915 AN XY: 694842

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

African (AFR) AF: 0.0282 AC: 898 AN: 31806

American (AMR) AF: 0.0139 AC: 547 AN: 39380

Ashkenazi Jewish (ASJ) AF: 0.0370 AC: 925 AN: 24976

East Asian (EAS) AF: 0.0218 AC: 816 AN: 37466

South Asian (SAS) AF: 0.0378 AC: 3087 AN: 81632

European-Finnish (FIN) AF: 0.0174 AC: 852 AN: 48972

Middle Eastern (MID) AF: 0.0226 AC: 95 AN: 4198

European-Non Finnish (NFE) AF: 0.0194 AC: 20865 AN: 1075066

Other (OTH) AF: 0.0209 AC: 1208 AN: 57908

⚠️ 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: 0.0298 AC: 4300 AN: 144206 Hom.: 73 Cov.: 0 AF XY: 0.0306 AC XY: 2139 AN XY: 69924

African (AFR) AF: 0.0346 AC: 1341 AN: 38746

American (AMR) AF: 0.0235 AC: 339 AN: 14420

Ashkenazi Jewish (ASJ) AF: 0.0543 AC: 184 AN: 3390

East Asian (EAS) AF: 0.0364 AC: 178 AN: 4890

South Asian (SAS) AF: 0.0498 AC: 218 AN: 4374

European-Finnish (FIN) AF: 0.0226 AC: 213 AN: 9432

Middle Eastern (MID) AF: 0.0496 AC: 14 AN: 282

European-Non Finnish (NFE) AF: 0.0267 AC: 1755 AN: 65788

Other (OTH) AF: 0.0220 AC: 44 AN: 1996

Alfa AF: 0.0316 Hom.: 744

ClinVar

ClinVar submissions

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)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10579871;

hg19: chr7-73467650;