7-74043176-C-T

Position:

• chr7-74043176-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000501.4(ELN):​c.427+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,586,356 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.014 (177 hom.)
• Consequence: ELN NM_000501.4 splice_region, intron
• Scores: Splicing: ADA: 0.0008024
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.12

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-74043176-C-T is Benign according to our data. Variant chr7-74043176-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74043176-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0105 (1591/152244) while in subpopulation AMR AF= 0.0171 (262/15286). AF 95% confidence interval is 0.0154. There are 14 homozygotes in gnomad4. There are 741 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1591 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELN	NM_000501.4	c.427+8C>T		splice_region_variant, intron_variant		ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.427+8C>T		splice_region_variant, intron_variant		1	NM_000501.4	ENSP00000252034.7

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1595 AN: 152126 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.0113 AC: 2256 AN: 199420 Hom.: 26 AF XY: 0.0119 AC XY: 1273 AN XY: 106948

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.000136

Gnomad SAS exome AF: 0.0155

Gnomad FIN exome AF: 0.00340

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0136 AC: 19513 AN: 1434112 Hom.: 177 Cov.: 32 AF XY: 0.0137 AC XY: 9721 AN XY: 710910

Gnomad4 AFR exome AF: 0.00228

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0232

Gnomad4 EAS exome AF: 0.0000782

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.00325

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0105 AC: 1591 AN: 152244 Hom.: 14 Cov.: 32 AF XY: 0.00995 AC XY: 741 AN XY: 74436

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.0171

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0107 Hom.: 5

Bravo AF: 0.0106

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 02, 2012	442+8C>T in intron 8 of ELN: This variant is not expected to have clinical signi ficance because it has been identified in 1.4% (101/7010) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs55868272). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Supravalvar aortic stenosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Cutis laxa, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.4
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00080
dbscSNV1_RF	Benign	0.032
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

Publications

LitVar

Other links and lift over

dbSNP: rs55868272; hg19: chr7-73457506;