7-74061134-A-G

Variant names:

• chr7-74061134-A-G
• rs782679448
• NM_000501.4:c.1781A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000501.4(ELN):​c.1781A>G​(p.Lys594Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K594I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.44
• Publications: 6 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33602405).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000501.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	NM_000501.4	MANE Select	c.1781A>G	p.Lys594Arg	missense	Exon 26 of 33	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1967A>G	p.Lys656Arg	missense	Exon 27 of 34	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1799A>G	p.Lys600Arg	missense	Exon 26 of 33	NP_001265844.1	P15502-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	ENST00000252034.12	TSL:1 MANE Select	c.1781A>G	p.Lys594Arg	missense	Exon 26 of 33	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1799A>G	p.Lys600Arg	missense	Exon 26 of 33	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1751A>G	p.Lys584Arg	missense	Exon 25 of 32	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251400 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.091
Sift	Benign	0.13	T
Sift4G	Benign	0.55	T
Polyphen		1.0	D
Vest4		0.51
MutPred		0.31		Loss of ubiquitination at K584 (P = 0.0244)
MVP		0.79
MPC		0.15
ClinPred		0.80	D
GERP RS		4.3
Varity_R		0.064
gMVP		0.63
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs782679448; hg19: chr7-73475464;