7-74069359-G-C

Variant names:

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

Variant summary

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

The ENST00000252034.12(ELN):​c.*659G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 236,352 control chromosomes in the GnomAD database, including 5,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4881 hom., cov: 32)
  • Exomes 𝑓: 0.12 (909 hom.)
• Consequence: ELN ENST00000252034.12 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-74069359-G-C is Benign according to our data. Variant chr7-74069359-G-C is described in ClinVar as Benign. ClinVar VariationId is 360677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000252034.12. 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>C		3_prime_UTR	Exon 33 of 33	NP_000492.2
	ELN	NM_001278939.2		c.*659G>C		3_prime_UTR	Exon 34 of 34	NP_001265868.1
	ELN	NM_001278915.2		c.*659G>C		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>C		3_prime_UTR	Exon 33 of 33	ENSP00000252034.7
	ELN	ENST00000458204.5	TSL:1	c.*659G>C		3_prime_UTR	Exon 32 of 32	ENSP00000403162.1
	ELN	ENST00000357036.9	TSL:1	c.*659G>C		3_prime_UTR	Exon 32 of 32	ENSP00000349540.5

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31321 AN: 151944 Hom.: 4856 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.0914

Gnomad FIN AF: 0.0985

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.173

GnomAD4 exome AF: 0.123 AC: 10337 AN: 84290 Hom.: 909 Cov.: 0 AF XY: 0.120 AC XY: 4666 AN XY: 38994

African (AFR) AF: 0.441 AC: 1723 AN: 3904

American (AMR) AF: 0.112 AC: 348 AN: 3102

Ashkenazi Jewish (ASJ) AF: 0.0819 AC: 421 AN: 5142

East Asian (EAS) AF: 0.0439 AC: 502 AN: 11440

South Asian (SAS) AF: 0.0835 AC: 76 AN: 910

European-Finnish (FIN) AF: 0.0743 AC: 48 AN: 646

Middle Eastern (MID) AF: 0.0927 AC: 46 AN: 496

European-Non Finnish (NFE) AF: 0.119 AC: 6155 AN: 51732

Other (OTH) AF: 0.147 AC: 1018 AN: 6918

GnomAD4 genome AF: 0.206 AC: 31392 AN: 152062 Hom.: 4881 Cov.: 32 AF XY: 0.202 AC XY: 15012 AN XY: 74332

African (AFR) AF: 0.443 AC: 18356 AN: 41432

American (AMR) AF: 0.134 AC: 2042 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 264 AN: 3468

East Asian (EAS) AF: 0.0526 AC: 272 AN: 5176

South Asian (SAS) AF: 0.0911 AC: 439 AN: 4820

European-Finnish (FIN) AF: 0.0985 AC: 1044 AN: 10594

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8418 AN: 67984

Other (OTH) AF: 0.171 AC: 361 AN: 2110

Alfa AF: 0.112 Hom.: 619

Bravo AF: 0.218

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.80
DANN	Benign	0.63
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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;