2-27079210-GC-G

Variant names:

• chr2-27079210-GC-G
• rs1445463863
• NM_007046.4:c.151delC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.235
• Publications: 0 publications found

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)

ACMG classification

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 id is 1527981.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMILIN1	NM_007046.4	c.151delC	p.Arg51GlyfsTer14	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.151delC	p.Arg51GlyfsTer14	frameshift_variant	Exon 1 of 8	1	NM_007046.4	ENSP00000369677.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1422734 Hom.: 0 Cov.: 31 AF XY: 0.00000706 AC XY: 5 AN XY: 708132

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

African (AFR) AF: 0.00 AC: 0 AN: 29908

American (AMR) AF: 0.0000287 AC: 1 AN: 34798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24474

East Asian (EAS) AF: 0.00 AC: 0 AN: 36900

South Asian (SAS) AF: 0.0000363 AC: 3 AN: 82534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1098468

Other (OTH) AF: 0.00 AC: 0 AN: 58566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arterial tortuosity Pathogenic:1

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Center for Medical Genetics Ghent, University of Ghent

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1445463863; hg19: chr2-27302078; COSMIC: COSV108230284; COSMIC: COSV108230284;