rs137854453

Positions:

• chr7-74060184-C-G
• chr7-74060184-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000501.4(ELN):​c.1621C>G​(p.Arg541Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELN NM_000501.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002869
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.417

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16405642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELN	NM_000501.4	c.1621C>G	p.Arg541Gly	missense_variant, splice_region_variant	24/33	ENST00000252034.12	NP_000492.2
ELN-AS1	NR_183555.1	n.72-152G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.1621C>G	p.Arg541Gly	missense_variant, splice_region_variant	24/33	1	NM_000501.4	ENSP00000252034	P4
ELN-AS1	ENST00000435932.2	n.79-152G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251370 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T;T;.;T;T;.;.;.;T;.;.;.;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.46	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	.;.;.;L;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;.;N;.;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.098
Sift	Benign	1.0	T;.;T;.;T;T;.;T;D;T;T;.;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;.;B;B;B;B;B;B;B;B;B;.
Vest4		0.37
MutPred		0.35		.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0095);.;.;.;.;.;
MVP		0.63
MPC		0.24
ClinPred		0.85	D
GERP RS		1.5
Varity_R		0.13
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.080		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: rs137854453; hg19: chr7-73474514;