rs41526244

chr7-74051926-G-Achr7-74051926-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V298A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: ELN NM_000501.4 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.27

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 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 GnomAd at 489 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.892G>A	p.Val298Ile	missense_variant, splice_region_variant	17/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 489 AN: 152190 Hom.: 1 Cov.: 32

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.: 1 AF XY: 0.000626 AC XY: 85 AN XY: 135890

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.: 4 Cov.: 31 AF XY: 0.000364 AC XY: 265 AN XY: 727140

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.: 1 Cov.: 32 AF XY: 0.00316 AC XY: 235 AN XY: 74474

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: 58

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00121 AC: 147

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
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	N
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	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.47	T
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	T
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

Other links and lift over

dbSNP: rs41526244; hg19: chr7-73466256;