19-18785055-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000095.3(COMP):c.1755G>A(p.Thr585Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0617 in 1,613,994 control chromosomes in the GnomAD database, including 3,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T585T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.048 ( 260 hom., cov: 31)

Exomes 𝑓: 0.063 ( 3358 hom. )

Consequence

COMP
NM_000095.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -4.27

Publications

10 publications found

Variant links:

Genes affected

COMP (HGNC:2227): (cartilage oligomeric matrix protein) The protein encoded by this gene is a noncollagenous extracellular matrix (ECM) protein. It consists of five identical glycoprotein subunits, each with EGF-like and calcium-binding (thrombospondin-like) domains. Oligomerization results from formation of a five-stranded coiled coil and disulfides. Binding to other ECM proteins such as collagen appears to depend on divalent cations. Contraction or expansion of a 5 aa aspartate repeat and other mutations can cause pseudochondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). [provided by RefSeq, Jul 2016]

COMP Gene-Disease associations (from GenCC):

COMP-related skeletal dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
multiple epiphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pseudoachondroplasia
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Illumina, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
multiple epiphyseal dysplasia type 1
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

COMP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 19-18785055-C-T is Benign according to our data. Variant chr19-18785055-C-T is described in ClinVar as Benign. ClinVar VariationId is 255119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000095.3. 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
	COMP	NM_000095.3	MANE Select	c.1755G>A	p.Thr585Thr	synonymous	Exon 16 of 19	NP_000086.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COMP	ENST00000222271.7	TSL:1 MANE Select	c.1755G>A	p.Thr585Thr	synonymous	Exon 16 of 19	ENSP00000222271.2	P49747-1
COMP	ENST00000542601.6	TSL:1	c.1656G>A	p.Thr552Thr	synonymous	Exon 15 of 18	ENSP00000439156.2	G3XAP6
COMP	ENST00000944187.1		c.1755G>A	p.Thr585Thr	synonymous	Exon 16 of 20	ENSP00000614246.1

Frequencies

GnomAD3 genomes

AF:

0.0476

AC:

7243

AN:

152050

Hom.:

260

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0317

Gnomad ASJ

AF:

0.0306

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0699

Gnomad OTH

AF:

0.0369

GnomAD2 exomes

AF:

0.0493

AC:

12397

AN:

251420

AF XY:

0.0498

show subpopulations

Gnomad AFR exome

AF:

0.0114

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.0291

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.0698

Gnomad OTH exome

AF:

0.0480

GnomAD4 exome

AF:

0.0631

AC:

92281

AN:

1461826

Hom.:

3358

Cov.:

AF XY:

0.0617

AC XY:

44866

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0106

AC:

355

AN:

33480

American (AMR)

AF:

0.0198

AC:

884

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0301

AC:

787

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39698

South Asian (SAS)

AF:

0.0152

AC:

1308

AN:

86258

European-Finnish (FIN)

AF:

0.118

AC:

6324

AN:

53396

Middle Eastern (MID)

AF:

0.00832

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0716

AC:

79593

AN:

1111974

Other (OTH)

AF:

0.0492

AC:

2974

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

5119

10238

15358

20477

25596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2870

5740

8610

11480

14350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0476

AC:

7242

AN:

152168

Hom.:

260

Cov.:

AF XY:

0.0477

AC XY:

3546

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0117

AC:

486

AN:

41510

American (AMR)

AF:

0.0317

AC:

484

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0306

AC:

106

AN:

3466

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.0139

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.119

AC:

1259

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0698

AC:

4748

AN:

67988

Other (OTH)

AF:

0.0365

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

368

737

1105

1474

1842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0580

Hom.:

158

Bravo

AF:

0.0394

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0589

EpiControl

AF:

0.0590

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Multiple epiphyseal dysplasia type 1 (1)

not specified (1)

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome (1)

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome;C1838280:Multiple epiphyseal dysplasia type 1;C5436916:Carpal tunnel syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

2.3

(source)

DANN

Benign

0.93

PhyloP100

-4.3

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over