NM_000501.4:c.196+194G>A

Variant names:

• chr7-74037933-G-A
• rs2301994
• NM_000501.4:c.196+194G>A

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.196+194G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0841 in 731,356 control chromosomes in the GnomAD database, including 3,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1334 hom., cov: 32)
  • Exomes 𝑓: 0.077 (2325 hom.)
• Consequence: ELN NM_000501.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.963
• Publications: 6 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=-0.86).
• BP6: Variant 7-74037933-G-A is Benign according to our data. Variant chr7-74037933-G-A is described in ClinVar as Benign. ClinVar VariationId is 674889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4	c.196+194G>A		intron_variant	Intron 4 of 32	ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.196+194G>A		intron_variant	Intron 4 of 32	1	NM_000501.4	ENSP00000252034.7

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17135 AN: 152032 Hom.: 1329 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0962

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.0923

GnomAD4 exome AF: 0.0766 AC: 44385 AN: 579206 Hom.: 2325 Cov.: 7 AF XY: 0.0772 AC XY: 23455 AN XY: 303808

African (AFR) AF: 0.212 AC: 3140 AN: 14824

American (AMR) AF: 0.117 AC: 2932 AN: 25110

Ashkenazi Jewish (ASJ) AF: 0.0312 AC: 489 AN: 15694

East Asian (EAS) AF: 0.206 AC: 6253 AN: 30422

South Asian (SAS) AF: 0.110 AC: 5784 AN: 52768

European-Finnish (FIN) AF: 0.0826 AC: 2509 AN: 30376

Middle Eastern (MID) AF: 0.0612 AC: 138 AN: 2254

European-Non Finnish (NFE) AF: 0.0546 AC: 20640 AN: 377816

Other (OTH) AF: 0.0835 AC: 2500 AN: 29942

GnomAD4 genome AF: 0.113 AC: 17150 AN: 152150 Hom.: 1334 Cov.: 32 AF XY: 0.115 AC XY: 8575 AN XY: 74374

African (AFR) AF: 0.208 AC: 8614 AN: 41498

American (AMR) AF: 0.108 AC: 1655 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3468

East Asian (EAS) AF: 0.210 AC: 1080 AN: 5148

South Asian (SAS) AF: 0.122 AC: 590 AN: 4820

European-Finnish (FIN) AF: 0.0962 AC: 1021 AN: 10618

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0563 AC: 3827 AN: 67994

Other (OTH) AF: 0.0923 AC: 195 AN: 2112

Alfa AF: 0.0728 Hom.: 291

Bravo AF: 0.119

Asia WGS AF: 0.174 AC: 603 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.70
PhyloP100		-0.96
PromoterAI		-0.019	Neutral
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: rs2301994; hg19: chr7-73452263;