chr16-55479419-G-C

Variant names:

• chr16-55479419-G-C
• rs2287073
• NM_004530.6:c.-61G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004530.6(MMP2):​c.-61G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,400,950 control chromosomes in the GnomAD database, including 8,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1061 hom., cov: 31)
  • Exomes 𝑓: 0.10 (7774 hom.)
• Consequence: MMP2 NM_004530.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.133
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-55479419-G-C is Benign according to our data. Variant chr16-55479419-G-C is described in ClinVar as [Benign]. Clinvar id is 319743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.-61G>C		5_prime_UTR_variant	Exon 1 of 13	ENST00000219070.9	NP_004521.1
MMP2	NM_001302508.1	c.-76+454G>C		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.-61G>C		5_prime_UTR_variant	Exon 1 of 13	1	NM_004530.6	ENSP00000219070.4
MMP2	ENST00000570308.5	c.-75-3490G>C		intron_variant	Intron 2 of 13	1		ENSP00000461421.1
MMP2	ENST00000568715.5	c.-76+454G>C		intron_variant	Intron 1 of 3	4		ENSP00000457949.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16558 AN: 151818 Hom.: 1062 Cov.: 31

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0919

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.137

GnomAD4 exome AF: 0.105 AC: 131148 AN: 1249024 Hom.: 7774 Cov.: 30 AF XY: 0.106 AC XY: 64208 AN XY: 607754

African (AFR) AF: 0.0639 AC: 1533 AN: 24008

American (AMR) AF: 0.172 AC: 2386 AN: 13834

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 2504 AN: 17306

East Asian (EAS) AF: 0.271 AC: 7925 AN: 29280

South Asian (SAS) AF: 0.106 AC: 6160 AN: 57878

European-Finnish (FIN) AF: 0.0912 AC: 3043 AN: 33370

Middle Eastern (MID) AF: 0.149 AC: 536 AN: 3606

European-Non Finnish (NFE) AF: 0.0993 AC: 101091 AN: 1018302

Other (OTH) AF: 0.116 AC: 5970 AN: 51440

GnomAD4 genome AF: 0.109 AC: 16557 AN: 151926 Hom.: 1061 Cov.: 31 AF XY: 0.110 AC XY: 8142 AN XY: 74250

African (AFR) AF: 0.0652 AC: 2707 AN: 41492

American (AMR) AF: 0.161 AC: 2457 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 480 AN: 3468

East Asian (EAS) AF: 0.259 AC: 1317 AN: 5094

South Asian (SAS) AF: 0.110 AC: 528 AN: 4820

European-Finnish (FIN) AF: 0.0919 AC: 972 AN: 10572

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.111 AC: 7539 AN: 67892

Other (OTH) AF: 0.136 AC: 287 AN: 2106

Alfa AF: 0.111 Hom.: 142

Bravo AF: 0.115

Asia WGS AF: 0.167 AC: 576 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multicentric osteolysis nodulosis arthropathy spectrum Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.5
DANN	Benign	0.77
PhyloP100		-0.13
PromoterAI		0.026	Neutral
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: rs2287073; hg19: chr16-55513331; COSMIC: COSV54604635; COSMIC: COSV54604635;