rs104893645

Positions:

• chr2-20005953-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000407540.8(MATN3):​c.581T>A​(p.Val194Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MATN3 ENST00000407540.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.10

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain VWFA (size 175) in uniprot entity MATN3_HUMAN there are 35 pathogenic changes around while only 7 benign (83%) in ENST00000407540.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 2-20005953-A-T is Pathogenic according to our data. Variant chr2-20005953-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 7540.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-20005953-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN3	NM_002381.5	c.581T>A	p.Val194Asp	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.581T>A	p.Val194Asp	missense_variant	2/8	1	NM_002381.5	ENSP00000383894	P1
MATN3	ENST00000421259.2	c.581T>A	p.Val194Asp	missense_variant	2/7	1		ENSP00000398753

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple epiphyseal dysplasia type 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2001

- -

Multiple epiphyseal dysplasia Other:1

not provided, no classification provided

literature only

GeneReviews

-

An MED mouse model harboring the p.Val194Asp pathogenic variant has demonstrated that the expression of this pathogenic variant causes ER stress and an unfolded protein response. Ultimately this results in a reduction in chondrocyte proliferation and dysregulated apoptosis [Leighton et al 2007, Nundlall et al 2010]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.93		Gain of disorder (P = 0.0188);Gain of disorder (P = 0.0188);
MVP		0.92
MPC		0.96
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

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

Other links and lift over

dbSNP: rs104893645; hg19: chr2-20205714;