rs121909497

Variant names:

• chr11-102955390-A-G
• rs121909497
• NM_002427.4:c.224T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_002427.4(MMP13):​c.224T>C​(p.Phe75Ser) 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 (★). ClinVar reports functional evidence for this variant: "SCV003440313: Experimental studies have shown that this missense change affects MMP13 function (PMID:16167086).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F75L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMP13 NM_002427.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.19
• Publications: 5 publications found

Genes affected

MMP13 (HGNC:7159): (matrix metallopeptidase 13) This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease cleaves type II collagen more efficiently than types I and III. It may be involved in articular cartilage turnover and cartilage pathophysiology associated with osteoarthritis. Mutations in this gene are associated with metaphyseal anadysplasia. This gene is part of a cluster of MMP genes on chromosome 11. [provided by RefSeq, Jan 2016]

MMP13 Gene-Disease associations (from GenCC):

• spondyloepimetaphyseal dysplasia, Missouri type

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• metaphyseal chondrodysplasia, Spahr type

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• metaphyseal anadysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003440313: Experimental studies have shown that this missense change affects MMP13 function (PMID: 16167086).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002427.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-102955391-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 998000.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 11-102955390-A-G is Pathogenic according to our data. Variant chr11-102955390-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9443.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002427.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP13	NM_002427.4	MANE Select	c.224T>C	p.Phe75Ser	missense	Exon 2 of 10	NP_002418.1	P45452

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP13	ENST00000260302.8	TSL:1 MANE Select	c.224T>C	p.Phe75Ser	missense	Exon 2 of 10	ENSP00000260302.3	P45452
	MMP13	ENST00000340273.4	TSL:1	c.224T>C	p.Phe75Ser	missense	Exon 2 of 11	ENSP00000339672.4	G5E971
	MMP13	ENST00000857540.1		c.224T>C	p.Phe75Ser	missense	Exon 2 of 10	ENSP00000527599.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Spondyloepimetaphyseal dysplasia, Missouri type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.83		Gain of disorder (P = 0.0021)
MVP		0.86
MPC		0.58
ClinPred		1.0	D
GERP RS		5.8
PromoterAI		-0.011	Neutral
Varity_R		0.89
gMVP		0.89
Mutation Taster		=15/85	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

Other links and lift over

dbSNP: rs121909497; hg19: chr11-102826119;