NM_000501.4:c.*659G>A

Variant names:

• chr7-74069359-G-A
• rs8326
• NM_000501.4:c.*659G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000501.4(ELN):​c.*659G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 236,408 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ELN NM_000501.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.663
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000283 (43/152102) while in subpopulation SAS AF = 0.00498 (24/4820). AF 95% confidence interval is 0.00343. There are 1 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 43 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	NM_000501.4	MANE Select	c.*659G>A		3_prime_UTR	Exon 33 of 33	NP_000492.2
	ELN	NM_001278939.2		c.*659G>A		3_prime_UTR	Exon 34 of 34	NP_001265868.1
	ELN	NM_001278915.2		c.*659G>A		3_prime_UTR	Exon 33 of 33	NP_001265844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	ENST00000252034.12	TSL:1 MANE Select	c.*659G>A		3_prime_UTR	Exon 33 of 33	ENSP00000252034.7
	ELN	ENST00000458204.5	TSL:1	c.*659G>A		3_prime_UTR	Exon 32 of 32	ENSP00000403162.1
	ELN	ENST00000357036.9	TSL:1	c.*659G>A		3_prime_UTR	Exon 32 of 32	ENSP00000349540.5

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 151984 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000202 AC: 17 AN: 84306 Hom.: 0 Cov.: 0 AF XY: 0.000179 AC XY: 7 AN XY: 39002

African (AFR) AF: 0.00 AC: 0 AN: 3906

American (AMR) AF: 0.00 AC: 0 AN: 3104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5144

East Asian (EAS) AF: 0.0000874 AC: 1 AN: 11440

South Asian (SAS) AF: 0.00879 AC: 8 AN: 910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 496

European-Non Finnish (NFE) AF: 0.000155 AC: 8 AN: 51738

Other (OTH) AF: 0.00 AC: 0 AN: 6922

GnomAD4 genome AF: 0.000283 AC: 43 AN: 152102 Hom.: 1 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74352

African (AFR) AF: 0.0000482 AC: 2 AN: 41454

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4820

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 619

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.87
PhyloP100		-0.66
Mutation Taster		=100/0	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: rs8326; hg19: chr7-73483689;