chr7-74059877-A-G

Variant names:

• chr7-74059877-A-G
• rs727503032
• ENST00000380562.8:c.1424A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BP6

The NM_001278915.2(ELN):​c.1424A>G​(p.Asn475Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELN NM_001278915.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.942
• 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-AS1 (HGNC:40212): (ELN antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 7-74059877-A-G is Benign according to our data. Variant chr7-74059877-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163393.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278915.2. 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.1415-9A>G		intron	N/A	NP_000492.2	P15502-2
	ELN	NM_001278915.2		c.1424A>G	p.Asn475Ser	missense	Exon 23 of 33	NP_001265844.1	P15502-1
	ELN	NM_001278939.2		c.1502-9A>G		intron	N/A	NP_001265868.1	P15502-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	ENST00000380562.8	TSL:1	c.1424A>G	p.Asn475Ser	missense	Exon 23 of 33	ENSP00000369936.4	P15502-1
	ELN	ENST00000252034.12	TSL:1 MANE Select	c.1415-9A>G		intron	N/A	ENSP00000252034.7	P15502-2
	ELN	ENST00000458204.5	TSL:1	c.1385-9A>G		intron	N/A	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 14

GnomAD4 genome Cov.: 32

Alfa AF: 0.000172 Hom.: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.3
DANN	Benign	0.40
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.94
PROVEAN	Benign	0.29	N
REVEL	Benign	0.019
Sift4G	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.057
MutPred		0.36		Gain of glycosylation at N475 (P = 0.0313)
MVP		0.076
ClinPred		0.018	T
GERP RS		-1.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 1
DS_AL_spliceai		0.24		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503032; hg19: chr7-73474207; COSMIC: COSV52710152; COSMIC: COSV52710152;