NM_004530.6:c.380+115A>G

Variant names:

• chr16-55483250-A-G
• rs1477017
• NM_004530.6:c.380+115A>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.380+115A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 769,062 control chromosomes in the GnomAD database, including 50,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10604 hom., cov: 32)
  • Exomes 𝑓: 0.36 (39696 hom.)
• Consequence: MMP2 NM_004530.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.507
• Publications: 31 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=-0.93).
• BP6: Variant 16-55483250-A-G is Benign according to our data. Variant chr16-55483250-A-G is described in ClinVar as Benign. ClinVar VariationId is 1266020.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.380+115A>G		intron_variant	Intron 2 of 12	ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.380+115A>G		intron_variant	Intron 2 of 12	1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56740 AN: 151898 Hom.: 10579 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.372

GnomAD4 exome AF: 0.356 AC: 219527 AN: 617046 Hom.: 39696 AF XY: 0.354 AC XY: 113056 AN XY: 319412

African (AFR) AF: 0.406 AC: 6288 AN: 15490

American (AMR) AF: 0.436 AC: 9459 AN: 21678

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 4659 AN: 15126

East Asian (EAS) AF: 0.283 AC: 9146 AN: 32290

South Asian (SAS) AF: 0.325 AC: 16551 AN: 50942

European-Finnish (FIN) AF: 0.320 AC: 14581 AN: 45580

Middle Eastern (MID) AF: 0.343 AC: 977 AN: 2850

European-Non Finnish (NFE) AF: 0.366 AC: 146894 AN: 401664

Other (OTH) AF: 0.349 AC: 10972 AN: 31426

GnomAD4 genome AF: 0.374 AC: 56800 AN: 152016 Hom.: 10604 Cov.: 32 AF XY: 0.371 AC XY: 27547 AN XY: 74292

African (AFR) AF: 0.411 AC: 17048 AN: 41448

American (AMR) AF: 0.425 AC: 6487 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1076 AN: 3464

East Asian (EAS) AF: 0.252 AC: 1296 AN: 5142

South Asian (SAS) AF: 0.311 AC: 1500 AN: 4820

European-Finnish (FIN) AF: 0.317 AC: 3345 AN: 10568

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24715 AN: 67986

Other (OTH) AF: 0.367 AC: 776 AN: 2112

Alfa AF: 0.367 Hom.: 16166

Bravo AF: 0.384

Asia WGS AF: 0.270 AC: 944 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.93
CADD	Benign	1.5
DANN	Benign	0.70
PhyloP100		-0.51
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: rs1477017; hg19: chr16-55517162;