7-74045245-G-T

Variant names:

• chr7-74045245-G-T
• rs61734581
• NM_000501.4:c.493G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000501.4(ELN):​c.493G>T​(p.Val165Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000844 in 1,614,168 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.69
• 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 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• supravalvular aortic stenosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal dominant cutis laxa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000306359 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008381695).
• BP6: Variant 7-74045245-G-T is Benign according to our data. Variant chr7-74045245-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193626.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 = 0.00437 (666/152376) while in subpopulation AFR AF = 0.0151 (626/41584). AF 95% confidence interval is 0.0141. There are 5 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 666 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.493G>T	p.Val165Leu	missense	Exon 10 of 33	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.493G>T	p.Val165Leu	missense	Exon 10 of 34	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.493G>T	p.Val165Leu	missense	Exon 10 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.493G>T	p.Val165Leu	missense	Exon 10 of 33	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.493G>T	p.Val165Leu	missense	Exon 10 of 33	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.463G>T	p.Val155Leu	missense	Exon 9 of 32	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 664 AN: 152258 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00133 AC: 330 AN: 248884 AF XY: 0.000816

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000476 AC: 696 AN: 1461792 Hom.: 4 Cov.: 31 AF XY: 0.000397 AC XY: 289 AN XY: 727196

African (AFR) AF: 0.0152 AC: 509 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1112006

Other (OTH) AF: 0.00126 AC: 76 AN: 60396

GnomAD4 genome AF: 0.00437 AC: 666 AN: 152376 Hom.: 5 Cov.: 33 AF XY: 0.00432 AC XY: 322 AN XY: 74520

African (AFR) AF: 0.0151 AC: 626 AN: 41584

American (AMR) AF: 0.00170 AC: 26 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.000931 Hom.: 1

Bravo AF: 0.00496

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00161 AC: 196

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)
-	-	1	Supravalvar aortic stenosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0084	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.24
Sift	Benign	0.036	D
Sift4G	Benign	0.53	T
Polyphen		0.99	D
Vest4		0.80
MutPred		0.14		Loss of catalytic residue at G154 (P = 0.4871)
MVP		0.86
MPC		0.18
ClinPred		0.034	T
GERP RS		3.8
Varity_R		0.087
gMVP		0.67
Mutation Taster		=98/2	polymorphism

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: rs61734581; hg19: chr7-73459575; COSMIC: COSV99333227; COSMIC: COSV99333227;