2-20005780-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002381.5(MATN3):c.754G>A(p.Glu252Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,605,932 control chromosomes in the GnomAD database, including 714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 40 hom., cov: 33)

Exomes 𝑓: 0.028 ( 674 hom. )

Consequence

MATN3
NM_002381.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.42

Publications

21 publications found

Variant links:

Genes affected

MATN3 (HGNC:6909): (matrilin 3) This gene encodes a member of von Willebrand factor A domain containing protein family. This family of proteins is thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This protein contains two von Willebrand factor A domains; it is present in the cartilage extracellular matrix and has a role in the development and homeostasis of cartilage and bone. Mutations in this gene result in multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

MATN3 Gene-Disease associations (from GenCC):

multiple epiphyseal dysplasia type 5
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
spondyloepimetaphyseal dysplasia, matrilin-3 type
Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

MATN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008475125).

BP6

Variant 2-20005780-C-T is Benign according to our data. Variant chr2-20005780-C-T is described in ClinVar as [Benign]. Clinvar id is 258648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0194 (2959/152282) while in subpopulation SAS AF = 0.0413 (199/4816). AF 95% confidence interval is 0.0366. There are 40 homozygotes in GnomAd4. There are 1471 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATN3	NM_002381.5 link	c.754G>A	p.Glu252Lys	missense_variant	Exon 2 of 8	ENST00000407540.8	NP_002372.1	O15232-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8 link	c.754G>A	p.Glu252Lys	missense_variant	Exon 2 of 8	1	NM_002381.5	ENSP00000383894.3		O15232-1
MATN3	ENST00000421259.2 link	c.754G>A	p.Glu252Lys	missense_variant	Exon 2 of 7	1		ENSP00000398753.2		O15232-2

Frequencies

GnomAD3 genomes

AF:

0.0194

AC:

2959

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0415

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0291

Gnomad OTH

AF:

0.0254

GnomAD2 exomes

AF:

0.0227

AC:

5472

AN:

241386

AF XY:

0.0251

show subpopulations

Gnomad AFR exome

AF:

0.00490

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.0160

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.0280

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0275

AC:

40010

AN:

1453650

Hom.:

674

Cov.:

AF XY:

0.0286

AC XY:

20625

AN XY:

721630

show subpopulations

African (AFR)

AF:

0.00375

AC:

125

AN:

33304

American (AMR)

AF:

0.0109

AC:

480

AN:

44004

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

424

AN:

25928

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39546

South Asian (SAS)

AF:

0.0449

AC:

3819

AN:

85020

European-Finnish (FIN)

AF:

0.0196

AC:

1041

AN:

53194

Middle Eastern (MID)

AF:

0.0308

AC:

177

AN:

5744

European-Non Finnish (NFE)

AF:

0.0293

AC:

32455

AN:

1106916

Other (OTH)

AF:

0.0248

AC:

1487

AN:

59994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1863

3727

5590

7454

9317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1214

2428

3642

4856

6070

<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:

0.0194

AC:

2959

AN:

152282

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1471

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00477

AC:

198

AN:

41548

American (AMR)

AF:

0.0154

AC:

236

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0413

AC:

199

AN:

4816

European-Finnish (FIN)

AF:

0.0211

AC:

224

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0291

AC:

1982

AN:

68026

Other (OTH)

AF:

0.0251

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

145

289

434

578

723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0255

Hom.:

154

Bravo

AF:

0.0178

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0283

AC:

109

ESP6500AA

AF:

0.00624

AC:

ESP6500EA

AF:

0.0280

AC:

232

ExAC

AF:

0.0228

AC:

2755

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 06, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Multiple epiphyseal dysplasia type 5

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Connective tissue disorder

Benign:1

May 12, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0085

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.8

L;L

PhyloP100

3.4

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.44

MPC

0.79

ClinPred

0.013

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.74

gMVP

0.93

Mutation Taster

=81/19

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

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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