rs28763986

Variant names:

• chr7-74057720-C-T
• rs28763986
• NM_000501.4:c.1414+24C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278939.2(ELN):​c.1501+24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,611,374 control chromosomes in the GnomAD database, including 259,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28146 hom., cov: 31)
  • Exomes 𝑓: 0.56 (231279 hom.)
• Consequence: ELN NM_001278939.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.37
• Publications: 13 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, G2P
• supravalvular aortic stenosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-74057720-C-T is Benign according to our data. Variant chr7-74057720-C-T is described in ClinVar as Benign. ClinVar VariationId is 1249499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278939.2. 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.1414+24C>T		intron	N/A	NP_000492.2
	ELN	NM_001278939.2		c.1501+24C>T		intron	N/A	NP_001265868.1
	ELN	NM_001278915.2		c.1414+24C>T		intron	N/A	NP_001265844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	ENST00000252034.12	TSL:1 MANE Select	c.1414+24C>T		intron	N/A	ENSP00000252034.7
	ELN	ENST00000380562.8	TSL:1	c.1414+24C>T		intron	N/A	ENSP00000369936.4
	ELN	ENST00000458204.5	TSL:1	c.1384+24C>T		intron	N/A	ENSP00000403162.1

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91768 AN: 151840 Hom.: 28115 Cov.: 31

Gnomad AFR AF: 0.694

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.576

GnomAD2 exomes AF: 0.590 AC: 147337 AN: 249772 AF XY: 0.592

Gnomad AFR exome AF: 0.699

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.522

Gnomad EAS exome AF: 0.712

Gnomad FIN exome AF: 0.598

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.560 AC: 817610 AN: 1459414 Hom.: 231279 Cov.: 43 AF XY: 0.564 AC XY: 409615 AN XY: 726036

African (AFR) AF: 0.698 AC: 23322 AN: 33406

American (AMR) AF: 0.574 AC: 25655 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13605 AN: 26126

East Asian (EAS) AF: 0.704 AC: 27936 AN: 39694

South Asian (SAS) AF: 0.673 AC: 57996 AN: 86166

European-Finnish (FIN) AF: 0.601 AC: 32081 AN: 53414

Middle Eastern (MID) AF: 0.585 AC: 2720 AN: 4646

European-Non Finnish (NFE) AF: 0.540 AC: 599767 AN: 1111052

Other (OTH) AF: 0.573 AC: 34528 AN: 60212

GnomAD4 genome AF: 0.604 AC: 91837 AN: 151960 Hom.: 28146 Cov.: 31 AF XY: 0.609 AC XY: 45210 AN XY: 74268

African (AFR) AF: 0.694 AC: 28782 AN: 41468

American (AMR) AF: 0.577 AC: 8811 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1796 AN: 3460

East Asian (EAS) AF: 0.701 AC: 3593 AN: 5124

South Asian (SAS) AF: 0.680 AC: 3274 AN: 4814

European-Finnish (FIN) AF: 0.606 AC: 6403 AN: 10570

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37279 AN: 67936

Other (OTH) AF: 0.570 AC: 1202 AN: 2108

Alfa AF: 0.565 Hom.: 35034

Bravo AF: 0.606

Asia WGS AF: 0.599 AC: 2083 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.11
DANN	Benign	0.63
PhyloP100		-1.4
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: rs28763986; hg19: chr7-73472050; COSMIC: COSV52709669; COSMIC: COSV52709669;