7-74060495-G-C

Variant names:

• chr7-74060495-G-C
• rs17855988
• NM_000501.4:c.1741G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_000501.4(ELN):​c.1741G>C​(p.Gly581Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0854 in 1,614,208 control chromosomes in the GnomAD database, including 6,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G581W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.062 (422 hom., cov: 33)
  • Exomes 𝑓: 0.088 (6308 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.24
• Publications: 37 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: Benign. The variant received -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-74060495-GG-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 1197278.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006361991).
• BP6: Variant 7-74060495-G-C is Benign according to our data. Variant chr7-74060495-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 177898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

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.1741G>C	p.Gly581Arg	missense	Exon 25 of 33	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1828G>C	p.Gly610Arg	missense	Exon 26 of 34	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1759G>C	p.Gly587Arg	missense	Exon 25 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.1741G>C	p.Gly581Arg	missense	Exon 25 of 33	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1759G>C	p.Gly587Arg	missense	Exon 25 of 33	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1711G>C	p.Gly571Arg	missense	Exon 24 of 32	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.0621 AC: 9458 AN: 152208 Hom.: 421 Cov.: 33

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0604

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0960

Gnomad OTH AF: 0.0750

GnomAD2 exomes AF: 0.0698 AC: 17545 AN: 251396 AF XY: 0.0732

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.0485

Gnomad ASJ exome AF: 0.0714

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0486

Gnomad NFE exome AF: 0.0991

Gnomad OTH exome AF: 0.0851

GnomAD4 exome AF: 0.0878 AC: 128382 AN: 1461882 Hom.: 6308 Cov.: 32 AF XY: 0.0877 AC XY: 63807 AN XY: 727236

African (AFR) AF: 0.0147 AC: 492 AN: 33480

American (AMR) AF: 0.0515 AC: 2302 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0725 AC: 1894 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0659 AC: 5683 AN: 86258

European-Finnish (FIN) AF: 0.0521 AC: 2783 AN: 53420

Middle Eastern (MID) AF: 0.0882 AC: 508 AN: 5762

European-Non Finnish (NFE) AF: 0.0988 AC: 109811 AN: 1112008

Other (OTH) AF: 0.0812 AC: 4903 AN: 60394

GnomAD4 genome AF: 0.0621 AC: 9457 AN: 152326 Hom.: 422 Cov.: 33 AF XY: 0.0578 AC XY: 4307 AN XY: 74480

African (AFR) AF: 0.0177 AC: 735 AN: 41594

American (AMR) AF: 0.0625 AC: 956 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 263 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0609 AC: 294 AN: 4828

European-Finnish (FIN) AF: 0.0383 AC: 407 AN: 10614

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0961 AC: 6533 AN: 68012

Other (OTH) AF: 0.0733 AC: 155 AN: 2114

Alfa AF: 0.0722 Hom.: 162

Bravo AF: 0.0613

TwinsUK AF: 0.0982 AC: 364

ALSPAC AF: 0.100 AC: 387

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.0995 AC: 856

ExAC AF: 0.0712 AC: 8638

Asia WGS AF: 0.0290 AC: 102 AN: 3478

EpiCase AF: 0.101

EpiControl AF: 0.103

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	2	Supravalvar aortic stenosis (2)
-	-	1	Cutis laxa, autosomal dominant (1)
-	-	1	Cutis laxa, autosomal dominant 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.40		Gain of methylation at G571 (P = 0.0126)
MPC		0.22
ClinPred		0.041	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.64
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs17855988; hg19: chr7-73474825; COSMIC: COSV52710379; COSMIC: COSV52710379;