NM_004530.6:c.530-334A>G

Variant names:

• chr16-55484965-A-G
• rs11646643
• NM_004530.6:c.530-334A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004530.6(MMP2):​c.530-334A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 151,982 control chromosomes in the GnomAD database, including 7,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.31 (7534 hom., cov: 31)
• Consequence: MMP2 NM_004530.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.970
• Publications: 20 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-55484965-A-G is Benign according to our data. Variant chr16-55484965-A-G is described in ClinVar as Benign. ClinVar VariationId is 1254989.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.530-334A>G		intron_variant	Intron 3 of 12	ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.530-334A>G		intron_variant	Intron 3 of 12	1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47164 AN: 151862 Hom.: 7527 Cov.: 31

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.314

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.310 AC: 47182 AN: 151982 Hom.: 7534 Cov.: 31 AF XY: 0.308 AC XY: 22851 AN XY: 74298

African (AFR) AF: 0.236 AC: 9784 AN: 41446

American (AMR) AF: 0.375 AC: 5720 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 901 AN: 3468

East Asian (EAS) AF: 0.146 AC: 755 AN: 5162

South Asian (SAS) AF: 0.249 AC: 1197 AN: 4816

European-Finnish (FIN) AF: 0.314 AC: 3324 AN: 10572

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.358 AC: 24304 AN: 67950

Other (OTH) AF: 0.309 AC: 651 AN: 2104

Alfa AF: 0.258 Hom.: 1004

Bravo AF: 0.311

Asia WGS AF: 0.194 AC: 676 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.050
DANN	Benign	0.73
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism (auto)

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: rs11646643; hg19: chr16-55518877;