rs77245812

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_002381.5(MATN3):c.908C>T(p.Thr303Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,613,922 control chromosomes in the GnomAD database, including 321 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. T303T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.012 ( 22 hom., cov: 33)

Exomes 𝑓: 0.016 ( 299 hom. )

Consequence

MATN3
NM_002381.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:7O:1

Conservation

PhyloP100: 9.32

Publications

24 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 links:

WDR35-DT (HGNC:55818): (WDR35 divergent transcript)

WDR35-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.018800974).

BP6

Variant 2-20003169-G-A is Benign according to our data. Variant chr2-20003169-G-A is described in ClinVar as Benign. ClinVar VariationId is 7542.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 = 0.0121 (1837/152310) while in subpopulation SAS AF = 0.0381 (184/4824). AF 95% confidence interval is 0.0336. There are 22 homozygotes in GnomAd4. There are 872 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATN3	NM_002381.5 link	c.908C>T	p.Thr303Met	missense_variant	Exon 3 of 8	ENST00000407540.8	NP_002372.1
WDR35-DT	NR_110235.1 link	n.364-851G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8 link	c.908C>T	p.Thr303Met	missense_variant	Exon 3 of 8	1	NM_002381.5	ENSP00000383894.3

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1840

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.0211

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0383

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0166

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0151

AC:

3771

AN:

249204

AF XY:

0.0171

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00519

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.00418

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

AF:

0.0162

AC:

23730

AN:

1461612

Hom.:

299

Cov.:

AF XY:

0.0171

AC XY:

12423

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.00254

AC:

AN:

33476

American (AMR)

AF:

0.00593

AC:

265

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

540

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39696

South Asian (SAS)

AF:

0.0443

AC:

3825

AN:

86248

European-Finnish (FIN)

AF:

0.00496

AC:

265

AN:

53386

Middle Eastern (MID)

AF:

0.0232

AC:

134

AN:

5766

European-Non Finnish (NFE)

AF:

0.0159

AC:

17689

AN:

1111816

Other (OTH)

AF:

0.0153

AC:

923

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1158

2317

3475

4634

5792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.0121

AC:

1837

AN:

152310

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

872

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00296

AC:

123

AN:

41574

American (AMR)

AF:

0.00954

AC:

146

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0211

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.0381

AC:

184

AN:

4824

European-Finnish (FIN)

AF:

0.00339

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0166

AC:

1129

AN:

68030

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

181

272

362

453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0148

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00494

AC:

ESP6500EA

AF:

0.0146

AC:

122

ExAC

AF:

0.0161

AC:

1950

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0173

EpiControl

AF:

0.0178

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple epiphyseal dysplasia type 5

Pathogenic:1Benign:1

Mar 06, 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. -

Jan 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 22, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spondyloepimetaphyseal dysplasia, matrilin-3 type;C1846843:Multiple epiphyseal dysplasia type 5;C3887526:Osteoarthritis susceptibility 2

Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Connective tissue disorder

Benign:1

Jan 31, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MATN3-related disorder

Benign:1

Mar 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Osteoarthritis susceptibility 2

Other:1

Jun 01, 2003

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.0054

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.019

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

3.3

PhyloP100

9.3

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.32

MPC

0.76

ClinPred

0.046

GERP RS

5.5

Varity_R

0.78

gMVP

0.80

Mutation Taster

=64/36

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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