7-74028118-G-C

Variant names:

• chr7-74028118-G-C
• rs537200597
• ENST00000869840.1:c.-70G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000445912.5(ELN):​c.-70G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000818 in 569,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00097 (0 hom.)
• Consequence: ELN ENST00000445912.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.927
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000974 (441/452546) while in subpopulation NFE AF = 0.0014 (427/304142). AF 95% confidence interval is 0.00129. There are 0 homozygotes in GnomAdExome4. There are 194 alleles in the male GnomAdExome4 subpopulation. Median coverage is 15. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 25 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000445912.5. 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.-70G>C		upstream_gene	N/A	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.-70G>C		upstream_gene	N/A	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.-70G>C		upstream_gene	N/A	NP_001265844.1	P15502-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	ENST00000869840.1		c.-70G>C		5_prime_UTR	Exon 1 of 33	ENSP00000539899.1
	ELN	ENST00000869804.1		c.-70G>C		5_prime_UTR	Exon 1 of 33	ENSP00000539863.1
	ELN	ENST00000869842.1		c.-70G>C		5_prime_UTR	Exon 1 of 33	ENSP00000539901.1

Frequencies

GnomAD3 genomes AF: 0.000214 AC: 25 AN: 117042 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000421

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000336

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000974 AC: 441 AN: 452546 Hom.: 0 Cov.: 15 AF XY: 0.000833 AC XY: 194 AN XY: 232840

African (AFR) AF: 0.000169 AC: 2 AN: 11824

American (AMR) AF: 0.000113 AC: 3 AN: 26526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10158

East Asian (EAS) AF: 0.00 AC: 0 AN: 9510

South Asian (SAS) AF: 0.00 AC: 0 AN: 50330

European-Finnish (FIN) AF: 0.000147 AC: 3 AN: 20344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2692

European-Non Finnish (NFE) AF: 0.00140 AC: 427 AN: 304142

Other (OTH) AF: 0.000353 AC: 6 AN: 17020

GnomAD4 genome AF: 0.000214 AC: 25 AN: 117042 Hom.: 0 Cov.: 29 AF XY: 0.000221 AC XY: 12 AN XY: 54266

African (AFR) AF: 0.0000325 AC: 1 AN: 30794

American (AMR) AF: 0.000421 AC: 4 AN: 9504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3148

East Asian (EAS) AF: 0.00 AC: 0 AN: 3378

South Asian (SAS) AF: 0.00 AC: 0 AN: 3172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.000336 AC: 20 AN: 59528

Other (OTH) AF: 0.00 AC: 0 AN: 1552

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cutis laxa, autosomal dominant (1)
-	1	-	Supravalvar aortic stenosis (1)
-	1	-	Supravalvar aortic stenosis;C0175702:Williams syndrome;C3276539:Cutis laxa, autosomal dominant 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		0.93
PromoterAI		-0.28	Neutral

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: rs537200597; hg19: chr7-73442448;