2-20003169-G-A

Position:

chr2-20003169-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000407540.8(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
ENST00000407540.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:6O:1

Conservation

PhyloP100: 9.32

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 7542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-20003169-G-A is described in Lovd as [Pathogenic]. Variant chr2-20003169-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN3	NM_002381.5 linkuse as main transcript	c.908C>T	p.Thr303Met	missense_variant	3/8	ENST00000407540.8	NP_002372.1
WDR35-DT	NR_110235.1 linkuse as main transcript	n.364-851G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8 linkuse as main transcript	c.908C>T	p.Thr303Met	missense_variant	3/8	1	NM_002381.5	ENSP00000383894	P1	O15232-1
MATN3	ENST00000421259.2 linkuse as main transcript	c.791-1089C>T		intron_variant		1		ENSP00000398753		O15232-2
WDR35-DT	ENST00000416575.2 linkuse as main transcript	n.357-851G>A		intron_variant, non_coding_transcript_variant		2
WDR35-DT	ENST00000658200.1 linkuse as main transcript	n.2226G>A		non_coding_transcript_exon_variant	3/3

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

GnomAD3 exomes

AF:

0.0151

AC:

3771

AN:

249204

Hom.:

AF XY:

0.0171

AC XY:

2312

AN XY:

135194

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 SAS exome

AF:

0.0444

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

Gnomad4 AFR exome

AF:

0.00254

Gnomad4 AMR exome

AF:

0.00593

Gnomad4 ASJ exome

AF:

0.0207

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0443

Gnomad4 FIN exome

AF:

0.00496

Gnomad4 NFE exome

AF:

0.0159

Gnomad4 OTH exome

AF:

0.0153

GnomAD4 genome

AF:

0.0121

AC:

1837

AN:

152310

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

872

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00296

Gnomad4 AMR

AF:

0.00954

Gnomad4 ASJ

AF:

0.0211

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0381

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.0166

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0153

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:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple epiphyseal dysplasia type 5

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 22, 2018

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 31, 2022

- -

MATN3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

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

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

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

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

MutationTaster

Benign

1.0

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over