chr7-74051947-G-A

Variant names:

• chr7-74051947-G-A
• rs1060503513
• NM_000501.4:c.913G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000501.4(ELN):​c.913G>A​(p.Ala305Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,286 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A305V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44
• Publications: 3 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38889208).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	NM_000501.4	MANE Select	c.913G>A	p.Ala305Thr	missense	Exon 17 of 33	NP_000492.2
	ELN	NM_001278939.2		c.913G>A	p.Ala305Thr	missense	Exon 17 of 34	NP_001265868.1
	ELN	NM_001278915.2		c.913G>A	p.Ala305Thr	missense	Exon 17 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.913G>A	p.Ala305Thr	missense	Exon 17 of 33	ENSP00000252034.7
	ELN	ENST00000380562.8	TSL:1	c.913G>A	p.Ala305Thr	missense	Exon 17 of 33	ENSP00000369936.4
	ELN	ENST00000458204.5	TSL:1	c.883G>A	p.Ala295Thr	missense	Exon 16 of 32	ENSP00000403162.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460286 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726492

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111854

Other (OTH) AF: 0.0000166 AC: 1 AN: 60282

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Supravalvar aortic stenosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.16
Sift	Benign	0.34	T
Sift4G	Benign	0.075	T
Polyphen		1.0	D
Vest4		0.39
MutPred		0.27		Gain of glycosylation at A295 (P = 0.0019)
MVP		0.80
MPC		0.18
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.071
gMVP		0.67
Mutation Taster		=89/11	polymorphism

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: rs1060503513; hg19: chr7-73466277;