chr2-27079183-A-AG

Variant names:

• chr2-27079183-A-AG
• rs758895857
• NM_007046.4:c.119dupG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PVS1 PP5_Moderate BS2

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
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.81

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]

ACMG classification

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	c.119dupG	p.Ser40ArgfsTer34	frameshift_variant	Exon 1 of 8	ENST00000380320.9	NP_008977.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 32

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: 2 AN: 206612 AF XY: 0.00000862

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: 62 AN: 1430584 Hom.: 0 Cov.: 31 AF XY: 0.0000477 AC XY: 34 AN XY: 712136

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 30560

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 37038

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24844

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 37398

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 83456

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51694

Gnomad4 NFE exome AF: 0.0000554 AC: 61 AN: 1100992

Gnomad4 Remaining exome AF: 0.0000170 AC: 1 AN: 58940

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241383 AN: 0.0000241383

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294126 AN: 0.0000294126

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

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
Mutation Taster		=24/176	disease causing (fs/PTC)

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

LitVar

Other links and lift over

dbSNP: rs758895857; hg19: chr2-27302051;