rs104893641

Variant names:

• chr2-20006152-C-G
• rs104893641
• NM_002381.5:c.382G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_002381.5(MATN3):​c.382G>C​(p.Ala128Pro) variant causes a missense change involving the alteration of a non-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). Synonymous variant affecting the same amino acid position (i.e. A128A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MATN3 NM_002381.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.78

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002381.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 2-20006152-C-G is Pathogenic according to our data. Variant chr2-20006152-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 7546.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-20006152-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATN3	NM_002381.5	c.382G>C	p.Ala128Pro	missense_variant	Exon 2 of 8	ENST00000407540.8	NP_002372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8	c.382G>C	p.Ala128Pro	missense_variant	Exon 2 of 8	1	NM_002381.5	ENSP00000383894.3
MATN3	ENST00000421259.2	c.382G>C	p.Ala128Pro	missense_variant	Exon 2 of 7	1		ENSP00000398753.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple epiphyseal dysplasia type 5 Pathogenic:1

Aug 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	4.0	H;H
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.96		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.98
MPC		0.85
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs104893641; hg19: chr2-20205913;