ENST00000570308.5:c.-76+4159T>G

Variant names:

• chr16-55468984-T-G
• rs893226
• ENST00000570308.5:c.-76+4159T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000570308.5(MMP2):​c.-76+4159T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 151,892 control chromosomes in the GnomAD database, including 25,616 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (25616 hom., cov: 31)
• Consequence: MMP2 ENST00000570308.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00400
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000570308.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	ENST00000570308.5	TSL:1	c.-76+4159T>G		intron	N/A	ENSP00000461421.1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88125 AN: 151774 Hom.: 25600 Cov.: 31

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.593

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

GnomAD4 genome AF: 0.581 AC: 88188 AN: 151892 Hom.: 25616 Cov.: 31 AF XY: 0.577 AC XY: 42846 AN XY: 74216

African (AFR) AF: 0.569 AC: 23567 AN: 41408

American (AMR) AF: 0.586 AC: 8959 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 1941 AN: 3472

East Asian (EAS) AF: 0.537 AC: 2749 AN: 5118

South Asian (SAS) AF: 0.496 AC: 2388 AN: 4816

European-Finnish (FIN) AF: 0.594 AC: 6270 AN: 10554

Middle Eastern (MID) AF: 0.596 AC: 174 AN: 292

European-Non Finnish (NFE) AF: 0.591 AC: 40173 AN: 67922

Other (OTH) AF: 0.593 AC: 1253 AN: 2112

Alfa AF: 0.583 Hom.: 11844

Bravo AF: 0.586

Asia WGS AF: 0.546 AC: 1898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	8.0
DANN	Benign	0.67
PhyloP100		-0.0040
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs893226; hg19: chr16-55502896;