rs2071307

Variant names:

• chr7-74056384-G-A
• rs2071307
• NM_000501.4:c.1264G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-74056384-G-A
• chr7-74056384-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000501.4(ELN):​c.1264G>A​(p.Gly422Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,613,756 control chromosomes in the GnomAD database, including 114,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. G422R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (8115 hom., cov: 31)
  • Exomes 𝑓: 0.37 (106346 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.709
• Publications: 77 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, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• supravalvular aortic stenosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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=5.096197E-4).
• BP6: Variant 7-74056384-G-A is Benign according to our data. Variant chr7-74056384-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 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.1264G>A	p.Gly422Ser	missense	Exon 20 of 33	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1264G>A	p.Gly422Ser	missense	Exon 20 of 34	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1264G>A	p.Gly422Ser	missense	Exon 20 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.1264G>A	p.Gly422Ser	missense	Exon 20 of 33	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1264G>A	p.Gly422Ser	missense	Exon 20 of 33	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1234G>A	p.Gly412Ser	missense	Exon 19 of 32	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46496 AN: 151764 Hom.: 8099 Cov.: 31

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.349

GnomAD2 exomes AF: 0.321 AC: 80822 AN: 251470 AF XY: 0.324

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.354

Gnomad NFE exome AF: 0.410

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.374 AC: 547143 AN: 1461870 Hom.: 106346 Cov.: 74 AF XY: 0.371 AC XY: 269755 AN XY: 727232

African (AFR) AF: 0.156 AC: 5233 AN: 33478

American (AMR) AF: 0.227 AC: 10143 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12051 AN: 26136

East Asian (EAS) AF: 0.155 AC: 6149 AN: 39700

South Asian (SAS) AF: 0.237 AC: 20476 AN: 86256

European-Finnish (FIN) AF: 0.357 AC: 19074 AN: 53420

Middle Eastern (MID) AF: 0.379 AC: 2187 AN: 5764

European-Non Finnish (NFE) AF: 0.405 AC: 450259 AN: 1111998

Other (OTH) AF: 0.357 AC: 21571 AN: 60394

GnomAD4 genome AF: 0.306 AC: 46541 AN: 151886 Hom.: 8115 Cov.: 31 AF XY: 0.301 AC XY: 22341 AN XY: 74206

African (AFR) AF: 0.165 AC: 6862 AN: 41474

American (AMR) AF: 0.276 AC: 4210 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1605 AN: 3468

East Asian (EAS) AF: 0.124 AC: 640 AN: 5156

South Asian (SAS) AF: 0.226 AC: 1088 AN: 4810

European-Finnish (FIN) AF: 0.345 AC: 3637 AN: 10538

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27224 AN: 67878

Other (OTH) AF: 0.356 AC: 752 AN: 2110

Alfa AF: 0.375 Hom.: 47317

Bravo AF: 0.297

TwinsUK AF: 0.408 AC: 1513

ALSPAC AF: 0.406 AC: 1564

ESP6500AA AF: 0.177 AC: 779

ESP6500EA AF: 0.413 AC: 3551

ExAC AF: 0.326 AC: 39602

Asia WGS AF: 0.244 AC: 847 AN: 3478

EpiCase AF: 0.406

EpiControl AF: 0.409

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Supravalvar aortic stenosis (2)
-	-	1	Cutis laxa, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.77
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.00051	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.71
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.038
Sift	Benign	0.13	T
Sift4G	Uncertain	0.042	D
Polyphen		0.012	B
Vest4		0.13
MPC		0.18
ClinPred		0.0019	T
GERP RS		1.2
Varity_R		0.021
gMVP		0.57
Mutation Taster		=98/2	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: rs2071307; hg19: chr7-73470714; COSMIC: COSV52708305; COSMIC: COSV52708305;