NM_004530.6:c.154-113T>A

Variant names:

• chr16-55482796-T-A
• rs857403
• NM_004530.6:c.154-113T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004530.6(MMP2):​c.154-113T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 918,598 control chromosomes in the GnomAD database, including 304,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46501 hom., cov: 32)
  • Exomes 𝑓: 0.82 (257921 hom.)
• Consequence: MMP2 NM_004530.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.77
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-55482796-T-A is Benign according to our data. Variant chr16-55482796-T-A is described in ClinVar as Benign. ClinVar VariationId is 1223276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.154-113T>A		intron_variant	Intron 1 of 12	ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.154-113T>A		intron_variant	Intron 1 of 12	1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118503 AN: 152006 Hom.: 46472 Cov.: 32

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.865

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.828

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.757

GnomAD4 exome AF: 0.819 AC: 627824 AN: 766474 Hom.: 257921 AF XY: 0.821 AC XY: 328325 AN XY: 400138

African (AFR) AF: 0.685 AC: 13617 AN: 19876

American (AMR) AF: 0.777 AC: 27377 AN: 35240

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 16637 AN: 21112

East Asian (EAS) AF: 0.725 AC: 24067 AN: 33174

South Asian (SAS) AF: 0.838 AC: 55982 AN: 66806

European-Finnish (FIN) AF: 0.818 AC: 32557 AN: 39796

Middle Eastern (MID) AF: 0.713 AC: 2345 AN: 3290

European-Non Finnish (NFE) AF: 0.834 AC: 425249 AN: 509662

Other (OTH) AF: 0.799 AC: 29993 AN: 37518

GnomAD4 genome AF: 0.780 AC: 118586 AN: 152124 Hom.: 46501 Cov.: 32 AF XY: 0.781 AC XY: 58056 AN XY: 74370

African (AFR) AF: 0.689 AC: 28603 AN: 41486

American (AMR) AF: 0.779 AC: 11914 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2754 AN: 3468

East Asian (EAS) AF: 0.685 AC: 3523 AN: 5146

South Asian (SAS) AF: 0.830 AC: 3999 AN: 4820

European-Finnish (FIN) AF: 0.828 AC: 8777 AN: 10596

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.830 AC: 56421 AN: 68004

Other (OTH) AF: 0.757 AC: 1597 AN: 2110

Alfa AF: 0.812 Hom.: 5917

Bravo AF: 0.771

Asia WGS AF: 0.753 AC: 2620 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

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	-0.88
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs857403; hg19: chr16-55516708;