Genetic Variant EMILIN1:p.Ala22Thr (chr2-27079129-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_007046.4(EMILIN1):c.64G>A(p.Ala22Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,603,660 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

EMILIN1
NM_007046.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.17

Publications

4 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_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMILIN1	NM_007046.4 link	c.64G>A	p.Ala22Thr	missense_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.64G>A	p.Ala22Thr	missense_variant	Exon 1 of 8	1	NM_007046.4	ENSP00000369677.4		Q9Y6C2-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000262

AC:

AN:

228902

AF XY:

0.0000158

show subpopulations

Gnomad AFR exome

AF:

0.0000770

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000896

AC:

AN:

1451416

Hom.:

Cov.:

AF XY:

0.00000969

AC XY:

AN XY:

722178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32536

American (AMR)

AF:

0.0000226

AC:

AN:

44180

Ashkenazi Jewish (ASJ)

AF:

0.0000388

AC:

AN:

25790

East Asian (EAS)

AF:

0.00

AC:

AN:

38102

South Asian (SAS)

AF:

0.0000582

AC:

AN:

85962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1107482

Other (OTH)

AF:

0.0000334

AC:

AN:

59834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67990

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neuronopathy, distal hereditary motor, autosomal dominant 10

Pathogenic:1

Oct 17, 2023

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Uncertain:1

May 29, 2013

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.80

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

PhyloP100

4.2

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.36

REVEL

Benign

0.24

Sift

Uncertain

0.026

Sift4G

Benign

0.41

Polyphen

0.25

Vest4

0.81

MutPred

0.21

Gain of glycosylation at A22 (P = 0.0012);

MVP

0.61

MPC

0.72

ClinPred

0.070

GERP RS

4.4

Varity_R

0.048

gMVP

0.44

Mutation Taster

=40/60

disease causing

(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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2-27079129-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over