rs140425210

chr7-74063194-G-Achr7-74063194-G-C

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.1828G>A(p.Gly610Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000521 in 1,609,756 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.92

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=0.009562254).
• BP6: Variant 7-74063194-G-A is Benign according to our data. Variant chr7-74063194-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00262 (399/152018) while in subpopulation AFR AF= 0.00914 (379/41466). AF 95% confidence interval is 0.00838. There are 3 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 399 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.1828G>A	p.Gly610Ser	missense_variant	27/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.1828G>A	p.Gly610Ser	missense_variant	27/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 399 AN: 151898 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000697 AC: 168 AN: 240874 Hom.: 0 AF XY: 0.000493 AC XY: 64 AN XY: 129872

Gnomad AFR exome AF: 0.00926

Gnomad AMR exome AF: 0.000446

Gnomad ASJ exome AF: 0.000207

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000549

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000302 AC: 440 AN: 1457738 Hom.: 0 Cov.: 33 AF XY: 0.000262 AC XY: 190 AN XY: 724480

Gnomad4 AFR exome AF: 0.00884

Gnomad4 AMR exome AF: 0.000680

Gnomad4 ASJ exome AF: 0.000348

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000355

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000930

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152018 Hom.: 3 Cov.: 32 AF XY: 0.00264 AC XY: 196 AN XY: 74272

Gnomad4 AFR AF: 0.00914

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.00300

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000816 AC: 99

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	This variant is associated with the following publications: (PMID: 23401415) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 02, 2017	- -

Supravalvar aortic stenosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 15, 2016

p.Gly610Ser in exon 27 of ELN: This variant is not expected to have clinical sig nificance because it has been identified in 1.1% (90/7766) of African chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs140425210). -

Cutis laxa, autosomal dominant 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	23
Dann	Benign	0.95
DEOGEN2	Benign	0.16	T;T;.;T;T;.;.;.;.;T;.;.;.;.;.
Eigen	Benign	-0.0078
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0096	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.97	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N;.;N;D;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.34	T;.;T;D;D;T;.;T;T;D;D;T;.;D;D
Sift4G	Uncertain	0.047	D;D;T;D;D;T;T;T;D;T;T;T;T;D;T
Polyphen		0.97	D;D;D;.;D;D;D;D;D;D;D;D;D;D;.
Vest4		0.40
MVP		0.75
MPC		0.18
ClinPred		0.032	T
GERP RS		3.8
Varity_R		0.067
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140425210; hg19: chr7-73477524;