rs140425210

Variant names:

• chr7-74063194-G-A
• rs140425210
• NM_000501.4:c.1828G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-74063194-G-A
• chr7-74063194-G-C

Variant summary

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

The NM_001278939.2(ELN):​c.2014G>A​(p.Gly672Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000521 in 1,609,756 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: ELN NM_001278939.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.92
• Publications: 11 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, G2P
• supravalvular aortic stenosis

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009562254).
• BP6: Variant 7-74063194-G-A is Benign according to our data. Variant chr7-74063194-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226631.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 = 0.00262 (399/152018) while in subpopulation AFR AF = 0.00914 (379/41466). AF 95% confidence interval is 0.00838. There are 3 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 399 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278939.2. 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.1828G>A	p.Gly610Ser	missense	Exon 27 of 33	NP_000492.2
	ELN	NM_001278939.2		c.2014G>A	p.Gly672Ser	missense	Exon 28 of 34	NP_001265868.1
	ELN	NM_001278915.2		c.1846G>A	p.Gly616Ser	missense	Exon 27 of 33	NP_001265844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	ENST00000252034.12	TSL:1 MANE Select	c.1828G>A	p.Gly610Ser	missense	Exon 27 of 33	ENSP00000252034.7
	ELN	ENST00000380562.8	TSL:1	c.1846G>A	p.Gly616Ser	missense	Exon 27 of 33	ENSP00000369936.4
	ELN	ENST00000458204.5	TSL:1	c.1798G>A	p.Gly600Ser	missense	Exon 26 of 32	ENSP00000403162.1

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 399 AN: 151898 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000697 AC: 168 AN: 240874 AF XY: 0.000493

Gnomad AFR exome AF: 0.00926

Gnomad AMR exome AF: 0.000446

Gnomad ASJ exome AF: 0.000207

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000549

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000302 AC: 440 AN: 1457738 Hom.: 0 Cov.: 33 AF XY: 0.000262 AC XY: 190 AN XY: 724480

African (AFR) AF: 0.00884 AC: 296 AN: 33474

American (AMR) AF: 0.000680 AC: 30 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.000348 AC: 9 AN: 25852

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39628

South Asian (SAS) AF: 0.0000355 AC: 3 AN: 84598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53076

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1110986

Other (OTH) AF: 0.000930 AC: 56 AN: 60240

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152018 Hom.: 3 Cov.: 32 AF XY: 0.00264 AC XY: 196 AN XY: 74272

African (AFR) AF: 0.00914 AC: 379 AN: 41466

American (AMR) AF: 0.000720 AC: 11 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67964

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.000696 Hom.: 1

Bravo AF: 0.00300

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000816 AC: 99

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.0078
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.10
Sift	Benign	0.34	T
Sift4G	Uncertain	0.047	D
Polyphen		0.97	D
Vest4		0.40
MVP		0.75
MPC		0.18
ClinPred		0.032	T
GERP RS		3.8
Varity_R		0.067
gMVP		0.49
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140425210; hg19: chr7-73477524;