7-74053320-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

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

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+50dupGT 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 0.13 (1264 hom., cov: 0)
  • Exomes 𝑓: 0.11 (4 hom.)
• Consequence: ELN NM_000501.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 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, 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-CTG is Benign according to our data. Variant chr7-74053320-C-CTG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360643.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.149 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+50dupGT		intron	N/A	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1096+49_1096+50dupGT		intron	N/A	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1096+49_1096+50dupGT		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+12insTG		intron	N/A	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1096+11_1096+12insTG		intron	N/A	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1066+11_1066+12insTG		intron	N/A	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.134 AC: 19364 AN: 144016 Hom.: 1263 Cov.: 0

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.0945

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.113 AC: 154927 AN: 1376902 Hom.: 4 Cov.: 0 AF XY: 0.112 AC XY: 76710 AN XY: 682936

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

African (AFR) AF: 0.0989 AC: 3126 AN: 31600

American (AMR) AF: 0.0798 AC: 3116 AN: 39024

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3133 AN: 24596

East Asian (EAS) AF: 0.0588 AC: 2192 AN: 37276

South Asian (SAS) AF: 0.103 AC: 8359 AN: 80804

European-Finnish (FIN) AF: 0.0845 AC: 4112 AN: 48658

Middle Eastern (MID) AF: 0.141 AC: 575 AN: 4092

European-Non Finnish (NFE) AF: 0.117 AC: 123688 AN: 1053922

Other (OTH) AF: 0.116 AC: 6626 AN: 56930

⚠️ 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: 0.134 AC: 19374 AN: 144118 Hom.: 1264 Cov.: 0 AF XY: 0.131 AC XY: 9130 AN XY: 69874

African (AFR) AF: 0.122 AC: 4725 AN: 38714

American (AMR) AF: 0.113 AC: 1629 AN: 14418

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 577 AN: 3390

East Asian (EAS) AF: 0.0939 AC: 459 AN: 4888

South Asian (SAS) AF: 0.133 AC: 581 AN: 4370

European-Finnish (FIN) AF: 0.101 AC: 954 AN: 9416

Middle Eastern (MID) AF: 0.206 AC: 58 AN: 282

European-Non Finnish (NFE) AF: 0.151 AC: 9956 AN: 65760

Other (OTH) AF: 0.144 AC: 286 AN: 1992

Alfa AF: 0.137 Hom.: 744

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Supravalvar aortic stenosis (3)
-	2	-	Cutis laxa, autosomal dominant (2)
-	-	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

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;