NM_000501.4:c.800-3C>G

Variant names:

• chr7-74051747-C-G
• rs397516433
• NM_000501.4:c.800-3C>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_000501.4(ELN):​c.800-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000060183: molecular studies showed abnormal splicing and skipping of exon 16 (Urban 1999, Wachi 2007)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELN NM_000501.4 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.33
• Publications: 4 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, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• supravalvular aortic stenosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000060183: molecular studies showed abnormal splicing and skipping of exon 16 (Urban 1999, Wachi 2007).; SCV006555883: Two different studies performed functional analysis on patient fibroblasts. Wachi and colleagues demonstrated that this variant causes skipping of exons 16-17 and results in stable mRNA (Wachi H et al., PMID: 17037986). They further concluded that tropolastin lacking these exons results in reduced self-association and altered elastic fiber formation. Conversely, Urban and colleagues showed generation of a cryptic splice that would lead to a frameshift and reduced expression, indicating haploinsufficiency (Urban Z et al., PMID: 10190324).; SCV000250041: Published functional studies demonstrate the production of aberrant mRNA lacking exons 16 and 17 in skin fibroblasts of affected individuals (Wachi et al., 2007); SCV000742567: Using mRNA studies, Urbán et al. (1999) and Wachi et al. (2007) demonstrated that c.800-3C>G alteration leads to aberrant splicing and exon skipping in the ELN gene. Additional studies by Wachi et al. (2007) showed that this aberrantly spliced transcript was able to synthesize a stable polypeptide that could interact with fibrillin-1 and fibulin-5 proteins, but was deficient in forming homotypic interactions. The alteration is predicted to affect splicing by in silico models: Based on BDGP and ESEfinder splice site in silico tools, this alteration is predicted to abolish the native splice acceptor site and is supported by molecular studies (see above).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-74051747-C-G is Pathogenic according to our data. Variant chr7-74051747-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 43586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.800-3C>G		splice_region intron	N/A	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.800-3C>G		splice_region intron	N/A	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.800-3C>G		splice_region 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.800-3C>G		splice_region intron	N/A	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.800-3C>G		splice_region intron	N/A	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.770-3C>G		splice_region intron	N/A	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Supravalvar aortic stenosis (4)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Benign	0.94
PhyloP100		2.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: -41
DS_AL_spliceai		0.90		Position offset: 3

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

Other links and lift over

dbSNP: rs397516433; hg19: chr7-73466077;