NM_000501.4:c.2T>A

Variant names:

• chr7-74028189-T-A
• NM_000501.4:c.2T>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000501.4(ELN):​c.2T>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ELN NM_000501.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-74028189-T-A is Pathogenic according to our data. Variant chr7-74028189-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3377152.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4	c.2T>A	p.Met1?	start_lost	Exon 1 of 33	ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.2T>A	p.Met1?	start_lost	Exon 1 of 33	1	NM_000501.4	ENSP00000252034.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Supravalvar aortic stenosis Pathogenic:1

Oct 11, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative is suggested and loss of function is a known mechanism of disease in this gene and are associated with autosomal dominant cutis laxa (ADCL; MIM#123700), and supravalvar aortic stenosis (SVAS; MIM#185500), respectively (PMID: 29501665). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMIDs: 19844261, 10942104, 31577255). (I) 0115 - Variants in this gene are known to have variable expressivity. Parents carriers have been reported with a milder presentation (PMIDs: 10942104, 31577255). (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0703 - Another start loss variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. c.1A>G; p.(Met1Val) has been reported once as pathogenic in ClinVar by a clinical laboratory, and reported in the literature in a family with supravalvular aortic stenosis (PMID: 10942104). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. c.2T>C; (p.Met1Thr) affects the same nucleotide and results in the loss of the start codon. This variant has been reported twice as pathogenic and once as likely pathogenic by clinical laboratories in ClinVar, and has been observed in a father and son affected with supravalvular aortic stenosis (PMID: 22740173). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;T;.;T;T;T;.;T;.;.;.;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
PROVEAN	Benign	-1.7	N;.;N;N;D;N;D;D;N;N;N;N;N;N;D;N;D;N;N;D;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.96	D;D;D;.;.;D;.;.;D;D;D;D;D;D;.;D;.;D;D;.;.
Vest4		0.87
MutPred		0.53		Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);Gain of ubiquitination at M1 (P = 0.0592);
MVP		0.84
ClinPred		0.90	D
GERP RS		4.5
Varity_R		0.59
gMVP		0.65

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-73442519;