Genetic Variant ELN:p.Ala380Ser (chr7-74054757-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000501.4(ELN):c.1138G>T(p.Ala380Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A380T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ELN
NM_000501.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.76

Publications

0 publications found

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]

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

ELN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29750502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4 link	c.1138G>T	p.Ala380Ser	missense_variant	Exon 19 of 33	ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12 link	c.1138G>T	p.Ala380Ser	missense_variant	Exon 19 of 33	1	NM_000501.4	ENSP00000252034.7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;T;.;T;T;.;.;.;.;T;.;.;.;.;.

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.53

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.30

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

.;.;N;N;.;.;N;.;.;.;.;.;.;N;N

PhyloP100

4.8

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.2

N;.;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.063

Sift

Benign

0.23

T;.;T;T;T;D;.;T;T;T;T;T;.;T;T

Sift4G

Benign

0.12

T;T;T;D;T;T;T;T;T;T;T;T;D;D;T

Polyphen

0.70

P;P;P;.;P;P;P;P;P;P;P;P;P;P;.

Vest4

0.53

MutPred

0.30

.;.;.;.;.;.;.;Gain of glycosylation at A370 (P = 0.0025);.;Gain of glycosylation at A370 (P = 0.0025);.;.;.;.;.;

MVP

0.62

MPC

0.17

ClinPred

0.64

GERP RS

3.1

Varity_R

0.052

gMVP

0.49

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over