chr16-55479279-C-G

Variant names:

• chr16-55479279-C-G
• rs886052124
• NM_004530.6:c.-201C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_004530.6(MMP2):​c.-201C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 134,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: MMP2 NM_004530.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000171 (23/134732) while in subpopulation NFE AF = 0.000224 (22/98426). AF 95% confidence interval is 0.000151. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 4. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004530.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	NM_004530.6	MANE Select	c.-201C>G		5_prime_UTR	Exon 1 of 13	NP_004521.1	P08253-1
	MMP2	NM_001302508.1		c.-76+314C>G		intron	N/A	NP_001289437.1	P08253-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	ENST00000219070.9	TSL:1 MANE Select	c.-201C>G		5_prime_UTR	Exon 1 of 13	ENSP00000219070.4	P08253-1
	MMP2	ENST00000570308.5	TSL:1	c.-75-3630C>G		intron	N/A	ENSP00000461421.1	P08253-2
	MMP2	ENST00000568715.5	TSL:4	c.-76+314C>G		intron	N/A	ENSP00000457949.1	H3BV48

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.000171 AC: 23 AN: 134732 Hom.: 0 Cov.: 4 AF XY: 0.000132 AC XY: 9 AN XY: 68282

African (AFR) AF: 0.00 AC: 0 AN: 3154

American (AMR) AF: 0.00 AC: 0 AN: 2594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3328

East Asian (EAS) AF: 0.00 AC: 0 AN: 8300

South Asian (SAS) AF: 0.00 AC: 0 AN: 2532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 542

European-Non Finnish (NFE) AF: 0.000224 AC: 22 AN: 98426

Other (OTH) AF: 0.000139 AC: 1 AN: 7220

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Multicentric osteolysis nodulosis arthropathy spectrum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.89
PhyloP100		1.8
PromoterAI		-0.13	Neutral

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: rs886052124; hg19: chr16-55513191;