7-74059903-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000501.4(ELN):c.1432G>T(p.Gly478Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000791 in 1,263,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G478S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

ELN
NM_000501.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.55

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 links:

ELN-AS1 (HGNC:40212): (ELN antisense RNA 1)

ELN-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.75

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ELN	NM_000501.4	MANE Select	c.1432G>T	p.Gly478Cys	missense	Exon 23 of 33	NP_000492.2	P15502-2
ELN	NM_001278939.2		c.1519G>T	p.Gly507Cys	missense	Exon 24 of 34	NP_001265868.1	P15502-3
ELN	NM_001278915.2		c.1450G>T	p.Gly484Cys	missense	Exon 23 of 33	NP_001265844.1	P15502-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ELN	ENST00000252034.12	TSL:1 MANE Select	c.1432G>T	p.Gly478Cys	missense	Exon 23 of 33	ENSP00000252034.7	P15502-2
ELN	ENST00000380562.8	TSL:1	c.1450G>T	p.Gly484Cys	missense	Exon 23 of 33	ENSP00000369936.4	P15502-1
ELN	ENST00000458204.5	TSL:1	c.1402G>T	p.Gly468Cys	missense	Exon 22 of 32	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.91e-7

AC:

AN:

1263440

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

638490

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29588

American (AMR)

AF:

0.00

AC:

AN:

44478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24896

East Asian (EAS)

AF:

0.00

AC:

AN:

38768

South Asian (SAS)

AF:

0.00

AC:

AN:

82366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5408

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

930906

Other (OTH)

AF:

0.00

AC:

AN:

53682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.038

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.7

PhyloP100

3.5

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.8

REVEL

Benign

0.28

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.78

MutPred

0.38

Gain of stability (P = 0.0841)

MVP

0.71

MPC

0.19

ClinPred

0.94

GERP RS

2.8

Varity_R

0.15

gMVP

0.66

Mutation Taster

=84/16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over