2-27079183-A-AG

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PVS1PP5_ModerateBS2

The NM_007046.4(EMILIN1):c.119dupG(p.Ser40ArgfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000411 in 1,582,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

EMILIN1
NM_007046.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 1.81

Publications

0 publications found

Variant links:

Genes affected

EMILIN1 (HGNC:19880): (elastin microfibril interfacer 1) This gene encodes an extracellular matrix glycoprotein that is characterized by an N-terminal microfibril interface domain, a coiled-coiled alpha-helical domain, a collagenous domain and a C-terminal globular C1q domain. The encoded protein associates with elastic fibers at the interface between elastin and microfibrils and may play a role in the development of elastic tissues including large blood vessels, dermis, heart and lung. [provided by RefSeq, Sep 2009]

EMILIN1 Gene-Disease associations (from GenCC):

neuronopathy, distal hereditary motor, autosomal dominant 10
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

EMILIN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-27079183-A-AG is Pathogenic according to our data. Variant chr2-27079183-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 1344492.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMILIN1	NM_007046.4 link	c.119dupG	p.Ser40ArgfsTer34	frameshift_variant	Exon 1 of 8	ENST00000380320.9	NP_008977.1	Q9Y6C2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMILIN1	ENST00000380320.9 link	c.119dupG	p.Ser40ArgfsTer34	frameshift_variant	Exon 1 of 8	1	NM_007046.4	ENSP00000369677.4		Q9Y6C2-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000968

AC:

AN:

206612

AF XY:

0.00000862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000215

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000433

AC:

AN:

1430584

Hom.:

Cov.:

AF XY:

0.0000477

AC XY:

AN XY:

712136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30560

American (AMR)

AF:

0.00

AC:

AN:

37038

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24844

East Asian (EAS)

AF:

0.00

AC:

AN:

37398

South Asian (SAS)

AF:

0.00

AC:

AN:

83456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.0000554

AC:

AN:

1100992

Other (OTH)

AF:

0.0000170

AC:

AN:

58940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Arterial tortuosity

Pathogenic:1

Center for Medical Genetics Ghent, University of Ghent

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:1

Feb 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (rs758895857, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Ser40Argfs*34) in the EMILIN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EMILIN1 are known to be pathogenic (PMID: 36351433). This premature translational stop signal has been observed in individual(s) with EMILIN1-related conditions (PMID: 36351433). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1344492). -

Arterial tortuosity-bone fragility syndrome

Pathogenic:1

Aug 02, 2024

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Mutation Taster

=24/176

disease causing (fs/PTC)

(source)

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

Publications

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2-27079183-A-AG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over