rs41526244

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000501.4(ELN):c.892G>A(p.Val298Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,613,972 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 4 hom. )

Consequence

ELN
NM_000501.4 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.27

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060070157).

BP6

Variant 7-74051926-G-A is Benign according to our data. Variant chr7-74051926-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74051926-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00321 (489/152308) while in subpopulation AFR AF= 0.011 (458/41574). AF 95% confidence interval is 0.0102. There are 1 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 489 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELN	NM_000501.4 linkuse as main transcript	c.892G>A	p.Val298Ile	missense_variant, splice_region_variant	17/33	ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12 linkuse as main transcript	c.892G>A	p.Val298Ile	missense_variant, splice_region_variant	17/33	1	NM_000501.4	ENSP00000252034	P4	P15502-2

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

489

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000967

AC:

243

AN:

251270

Hom.:

AF XY:

0.000626

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000407

AC:

595

AN:

1461664

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

265

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.0116

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000764

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.00321

AC:

489

AN:

152308

Hom.:

Cov.:

AF XY:

0.00316

AC XY:

235

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0110

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.0118

Hom.:

842

Bravo

AF:

0.00358

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00121

AC:

147

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ELN: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	This variant is associated with the following publications: (PMID: 29332214) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 11, 2016

- -

Supravalvar aortic stenosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.11

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

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.57

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

MetaRNN

Benign

0.0060

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;.;L;L;.;.;.;.;L;.;.;.;.;.;.;L;L

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.49

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

REVEL

Benign

0.063

Sift

Benign

0.084

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

Sift4G

Benign

0.39

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

Polyphen

0.47

P;P;P;.;B;.;.;P;P;P;B;P;P;P;P;P;.

Vest4

0.15

MVP

0.32

MPC

0.15

ClinPred

0.026

GERP RS

5.0

Varity_R

0.041

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over