Genetic Variant EMILIN1:p.Arg51GlyfsTer14 (chr2-27079210-GC-G) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_007046.4(EMILIN1):c.151delC(p.Arg51GlyfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000422 in 1,422,734 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

EMILIN1
NM_007046.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.235

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):

arterial tortuosity-bone fragility syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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 9 ACMG points.

PVS1

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

PP5

Variant 2-27079210-GC-G is Pathogenic according to our data. Variant chr2-27079210-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1527981.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007046.4. 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
	EMILIN1	NM_007046.4	MANE Select	c.151delC	p.Arg51GlyfsTer14	frameshift	Exon 1 of 8	NP_008977.1	Q9Y6C2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EMILIN1	ENST00000380320.9	TSL:1 MANE Select	c.151delC	p.Arg51GlyfsTer14	frameshift	Exon 1 of 8	ENSP00000369677.4	Q9Y6C2-1
EMILIN1	ENST00000957377.1		c.151delC	p.Arg51GlyfsTer14	frameshift	Exon 1 of 8	ENSP00000627436.1
EMILIN1	ENST00000957375.1		c.151delC	p.Arg51GlyfsTer14	frameshift	Exon 1 of 7	ENSP00000627434.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000422

AC:

AN:

1422734

Hom.:

Cov.:

AF XY:

0.00000706

AC XY:

AN XY:

708132

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29908

American (AMR)

AF:

0.0000287

AC:

AN:

34798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24474

East Asian (EAS)

AF:

0.00

AC:

AN:

36900

South Asian (SAS)

AF:

0.0000363

AC:

AN:

82534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1098468

Other (OTH)

AF:

0.00

AC:

AN:

58566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000412196), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

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>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arterial tortuosity (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.23

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over