16-55471128-T-G

Variant names:

• chr16-55471128-T-G
• rs1347653
• ENST00000570308.5:c.-76+6303T>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+6303T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.798 in 152,148 control chromosomes in the GnomAD database, including 48,634 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 0.80 (48634 hom., cov: 31)
• Consequence: MMP2 ENST00000570308.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.841 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+6303T>G		intron	N/A	ENSP00000461421.1

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121258 AN: 152028 Hom.: 48595 Cov.: 31

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.854

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.760

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.817

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

GnomAD4 genome AF: 0.798 AC: 121352 AN: 152148 Hom.: 48634 Cov.: 31 AF XY: 0.794 AC XY: 59050 AN XY: 74380

African (AFR) AF: 0.724 AC: 30062 AN: 41504

American (AMR) AF: 0.853 AC: 13055 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2615 AN: 3470

East Asian (EAS) AF: 0.746 AC: 3853 AN: 5166

South Asian (SAS) AF: 0.759 AC: 3651 AN: 4812

European-Finnish (FIN) AF: 0.785 AC: 8317 AN: 10596

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57021 AN: 67994

Other (OTH) AF: 0.818 AC: 1723 AN: 2106

Alfa AF: 0.830 Hom.: 85856

Bravo AF: 0.802

Asia WGS AF: 0.763 AC: 2654 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.7
DANN	Benign	0.68
PhyloP100		0.084
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: rs1347653; hg19: chr16-55505040;