rs41523046

Variant names:

• chr7-74059978-G-A
• rs41523046
• NM_000501.4:c.1507G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-74059978-G-A
• chr7-74059978-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000501.4(ELN):​c.1507G>A​(p.Val503Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,613,372 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V503L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.373
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023728043).
• BP6: Variant 7-74059978-G-A is Benign according to our data. Variant chr7-74059978-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000573 (87/151764) while in subpopulation NFE AF = 0.00109 (74/67854). AF 95% confidence interval is 0.000891. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 87 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.1507G>A	p.Val503Met	missense	Exon 23 of 33	NP_000492.2	P15502-2
	ELN	NM_001278939.2		c.1594G>A	p.Val532Met	missense	Exon 24 of 34	NP_001265868.1	P15502-3
	ELN	NM_001278915.2		c.1525G>A	p.Val509Met	missense	Exon 23 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.1507G>A	p.Val503Met	missense	Exon 23 of 33	ENSP00000252034.7	P15502-2
	ELN	ENST00000380562.8	TSL:1	c.1525G>A	p.Val509Met	missense	Exon 23 of 33	ENSP00000369936.4	P15502-1
	ELN	ENST00000458204.5	TSL:1	c.1477G>A	p.Val493Met	missense	Exon 22 of 32	ENSP00000403162.1	E7EN65

Frequencies

GnomAD3 genomes AF: 0.000574 AC: 87 AN: 151652 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000626

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000469 AC: 118 AN: 251454 AF XY: 0.000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000993

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000702 AC: 1026 AN: 1461608 Hom.: 1 Cov.: 31 AF XY: 0.000640 AC XY: 465 AN XY: 727116

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86244

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000862 AC: 958 AN: 1111838

Other (OTH) AF: 0.000696 AC: 42 AN: 60380

GnomAD4 genome AF: 0.000573 AC: 87 AN: 151764 Hom.: 0 Cov.: 32 AF XY: 0.000499 AC XY: 37 AN XY: 74198

African (AFR) AF: 0.000145 AC: 6 AN: 41380

American (AMR) AF: 0.000197 AC: 3 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000626 AC: 3 AN: 4790

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 67854

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000446

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000568 AC: 69

EpiCase AF: 0.000818

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	Supravalvar aortic stenosis (2)
-	-	1	Cutis laxa, autosomal dominant 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.042	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.37
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.063
Sift	Benign	0.075	T
Sift4G	Benign	0.23	T
Polyphen		0.94	P
Vest4		0.35
MVP		0.43
MPC		0.18
ClinPred		0.026	T
GERP RS		-0.27
Varity_R		0.041
gMVP		0.48
Mutation Taster		=92/8	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: rs41523046; hg19: chr7-73474308;