7-74028188-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000501.4(ELN):c.1A>G(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ELN NM_000501.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.47

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 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000501.4 (ELN) was described as [Likely_pathogenic] in ClinVar as 213185
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-74028188-A-G is Pathogenic according to our data. Variant chr7-74028188-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2735031.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.1A>G	p.Met1?	start_lost	1/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.1A>G	p.Met1?	start_lost	1/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Supravalvar aortic stenosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2023

This sequence change affects the initiator methionine of the ELN mRNA. There are no downstream in-frame methionine residues; therefore, it is expected to result in an absent or disrupted protein product. Loss-of-function variants in ELN are known to be pathogenic (PMID: 9215670, 11175284). This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with syndromic structural heart defects (PMID: 10942104, 22740173). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;.;T;T;T;.;T;.;.;.;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.75	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	0.95	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-0.93	N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.67
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		0.81	P;P;P;.;.;P;.;.;P;P;P;P;P;P;.;P;.;P;P;.;.
Vest4		0.87
MutPred		0.52		Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);
MVP		0.81
ClinPred		0.82	D
GERP RS		4.5
Varity_R		0.26
gMVP		0.41

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: chr7-73442518;