rs886052124

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.-201C>G		5_prime_UTR_variant	Exon 1 of 13	ENST00000219070.9	NP_004521.1
MMP2	NM_001302508.1	c.-76+314C>G		intron_variant	Intron 1 of 12		NP_001289437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.-201C>G		5_prime_UTR_variant	Exon 1 of 13	1	NM_004530.6	ENSP00000219070.4
MMP2	ENST00000570308.5	c.-75-3630C>G		intron_variant	Intron 2 of 13	1		ENSP00000461421.1
MMP2	ENST00000568715.5	c.-76+314C>G		intron_variant	Intron 1 of 3	4		ENSP00000457949.1

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multicentric osteolysis nodulosis arthropathy spectrum Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

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;