rs397515546

Positions:

• chr2-20006175-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_002381.5(MATN3):​c.359C>T​(p.Thr120Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MATN3 NM_002381.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain VWFA (size 175) in uniprot entity MATN3_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_002381.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 2-20006175-G-A is Pathogenic according to our data. Variant chr2-20006175-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-20006175-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN3	NM_002381.5	c.359C>T	p.Thr120Met	missense_variant	2/8	ENST00000407540.8	NP_002372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8	c.359C>T	p.Thr120Met	missense_variant	2/8	1	NM_002381.5	ENSP00000383894	P1
MATN3	ENST00000421259.2	c.359C>T	p.Thr120Met	missense_variant	2/7	1		ENSP00000398753

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461644 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 24, 2021	This sequence change replaces threonine with methionine at codon 120 of the MATN3 protein (p.Thr120Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with multiple epiphyseal dysplasia (PMID: 14729835, 21965141, 15459972). It has been observed to segregate with disease in related individuals; however it has also been observed in reportedly unaffected family members, suggesting reduced penetrance. ClinVar contains an entry for this variant (Variation ID: 65664). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2018	- -

Spondyloepimetaphyseal dysplasia, matrilin-3 type Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.T120M in MATN3 (NM_002381.5) has been reported in multiple affected individuals and shows incomplete penetrance (Mabuchi A et al,Jackson GC et al,Kim OH et al). It has been submitted to ClinVar as Pathogenic. The p.T120M variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.T120M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 120 of MATN3 is conserved in all mammalian species. The nucleotide c.359 in MATN3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -

Multiple epiphyseal dysplasia type 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.T120M in MATN3 (NM_002381.5) has been reported in multiple affected individuals and shows incomplete penetrance (Mabuchi A et al; Jackson GC et al; Kim OH et al). It has been submitted to ClinVar as Pathogenic.The p.T120M variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.T120M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 120 of MATN3 is conserved in all mammalian species. The nucleotide c.359 in MATN3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -

Multiple epiphyseal dysplasia Other:1

not provided, no classification provided

literature only

GeneReviews

-

European-based studies have identified p.Arg121Trp in 12/33 and p.Thr120Met in 5/33 affected individuals (total = 52%) [Chapman et al 2001; Mostert et al 2003; Jackson et al 2004; Cotterill et al 2005; Fresquet et al 2007; Jackson et al 2012; Author, unpublished data]. In a Japanese population, p.Arg121Trp was identified in 3/9 and p.Thr120Met in 3/9 affected individuals (total = 66%) [Mabuchi et al 2004, Itoh et al 2006]. In a Korean study, p.Arg121Trp was identified in 20/30 and p.Thr120Met was identified in 4/30 affected individuals (total = 80%) [Kim et al 2011]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.89		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.98
MPC		0.76
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs397515546; hg19: chr2-20205936; COSMIC: COSV68100368; COSMIC: COSV68100368;