chr7-74028188-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_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

Scores

6
6
4

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.47
Variant links:
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]

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ACMG classification

Classification made for transcript

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
ELNNM_000501.4 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/33 ENST00000252034.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ELNENST00000252034.12 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/331 NM_000501.4 P4P15502-2

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
LINK: link

Submissions by phenotype

Supravalvar aortic stenosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 05, 2023This 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; API