rs121912954

Variant names:

• chr16-55485677-C-A
• rs121912954
• NM_004530.6:c.732C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-55485677-C-A
• chr16-55485677-C-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004530.6(MMP2):​c.732C>A​(p.Tyr244*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMP2 NM_004530.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.431
• Publications: 6 publications found

Genes affected

MMP2 (HGNC:7166): (matrix metallopeptidase 2) This gene is a member of the matrix metalloproteinase (MMP) gene family, that are zinc-dependent enzymes capable of cleaving components of the extracellular matrix and molecules involved in signal transduction. The protein encoded by this gene is a gelatinase A, type IV collagenase, that contains three fibronectin type II repeats in its catalytic site that allow binding of denatured type IV and V collagen and elastin. Unlike most MMP family members, activation of this protein can occur on the cell membrane. This enzyme can be activated extracellularly by proteases, or, intracellulary by its S-glutathiolation with no requirement for proteolytical removal of the pro-domain. This protein is thought to be involved in multiple pathways including roles in the nervous system, endometrial menstrual breakdown, regulation of vascularization, and metastasis. Mutations in this gene have been associated with Winchester syndrome and Nodulosis-Arthropathy-Osteolysis (NAO) syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

MMP2 Gene-Disease associations (from GenCC):

• multicentric osteolysis, nodulosis, and arthropathy

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• multicentric osteolysis-nodulosis-arthropathy spectrum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-55485677-C-A is Pathogenic according to our data. Variant chr16-55485677-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 17109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.732C>A	p.Tyr244*	stop_gained	Exon 5 of 13	ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.732C>A	p.Tyr244*	stop_gained	Exon 5 of 13	1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multicentric osteolysis, nodulosis, and arthropathy Pathogenic:3

Apr 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2 -

Jul 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multicentric osteolysis nodulosis arthropathy spectrum Pathogenic:1

Jan 31, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:1

May 12, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		0.43
Vest4		0.97
GERP RS		3.7
Mutation Taster		=0/200	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: rs121912954; hg19: chr16-55519589;