chr7-74042984-G-A

Variant names:

• chr7-74042984-G-A
• rs145519139
• NM_000501.4:c.326G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_000501.4(ELN):​c.326G>A​(p.Gly109Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,614,174 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G109G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: ELN NM_000501.4 missense, splice_region
• Scores: Splicing: ADA: 0.8944
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.55
• Publications: 2 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

ENSG00000306359 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30419254).
• BP6: Variant 7-74042984-G-A is Benign according to our data. Variant chr7-74042984-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213171.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000368 (56/152282) while in subpopulation NFE AF = 0.000676 (46/68028). AF 95% confidence interval is 0.000521. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 56 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	NM_000501.4	MANE Select	c.326G>A	p.Gly109Asp	missense splice_region	Exon 7 of 33	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.326G>A	p.Gly109Asp	missense splice_region	Exon 7 of 34	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.326G>A	p.Gly109Asp	missense splice_region	Exon 7 of 33	NP_001265844.1	P15502-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	ENST00000252034.12	TSL:1 MANE Select	c.326G>A	p.Gly109Asp	missense splice_region	Exon 7 of 33	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.326G>A	p.Gly109Asp	missense splice_region	Exon 7 of 33	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.296G>A	p.Gly99Asp	missense splice_region	Exon 6 of 32	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000676

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000362 AC: 91 AN: 251468 AF XY: 0.000405

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000415 AC: 606 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000397 AC XY: 289 AN XY: 727248

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000491 AC: 546 AN: 1112010

Other (OTH) AF: 0.000381 AC: 23 AN: 60396

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74460

African (AFR) AF: 0.000144 AC: 6 AN: 41556

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000509 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000395 AC: 48

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Supravalvar aortic stenosis (2)
-	1	-	Cardiomyopathy (1)
-	-	1	Cutis laxa, autosomal dominant 1 (1)
-	-	1	ELN-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.70
MVP		0.78
MPC		0.24
ClinPred		0.14	T
GERP RS		4.9
Varity_R		0.076
gMVP		0.78
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.050		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: rs145519139; hg19: chr7-73457314;