rs41376344

chr7-74051965-G-Achr7-74051965-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000501.4(ELN):c.931G>A(p.Ala311Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000573 in 1,613,572 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (6 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.75

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000501.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.007754147).
• BP6: Variant 7-74051965-G-A is Benign according to our data. Variant chr7-74051965-G-A is described in ClinVar as [Benign]. Clinvar id is 360642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000519 (79/152318) while in subpopulation EAS AF= 0.013 (67/5172). AF 95% confidence interval is 0.0105. There are 1 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.931G>A	p.Ala311Thr	missense_variant	17/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.931G>A	p.Ala311Thr	missense_variant	17/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00115 AC: 288 AN: 250306 Hom.: 4 AF XY: 0.00106 AC XY: 144 AN XY: 135586

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0144

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000578 AC: 845 AN: 1461254 Hom.: 6 Cov.: 31 AF XY: 0.000586 AC XY: 426 AN XY: 726928

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0171

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74480

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0130

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000314 Hom.: 1

Bravo AF: 0.000793

ExAC AF: 0.00114 AC: 138

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Supravalvar aortic stenosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cutis laxa, autosomal dominant 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.;T;T;.;.;.;.;.;T;.;.;.;.;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.54	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0078	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.68	D;D;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.7	N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;.;D;D;D;D;D;.;D;D
Sift4G	Uncertain	0.015	D;T;D;T;T;D;T;D;T;T;D;T;T;D;D;D
Polyphen		0.97	D;D;D;.;D;.;D;D;D;D;D;D;D;D;D;.
Vest4		0.51
MVP		0.74
MPC		0.18
ClinPred		0.068	T
GERP RS		3.9
Varity_R		0.043
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41376344; hg19: chr7-73466295;