16-55479032-G-T

Variant names:

• chr16-55479032-G-T
• rs17859829
• ENST00000570308.5:c.-75-3877G>T

Variant summary

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

The NM_001302508.1(MMP2):​c.-76+67G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0568 in 142,864 control chromosomes in the GnomAD database, including 308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (306 hom., cov: 31)
  • Exomes 𝑓: 0.038 (2 hom.)
• Consequence: MMP2 NM_001302508.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.148
• Publications: 1 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=-0.81).
• BP6: Variant 16-55479032-G-T is Benign according to our data. Variant chr16-55479032-G-T is described in ClinVar as [Benign]. Clinvar id is 1280738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_001302508.1	c.-76+67G>T		intron_variant	Intron 1 of 12		NP_001289437.1
MMP2	NM_004530.6	c.-448G>T		upstream_gene_variant		ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000570308.5	c.-75-3877G>T		intron_variant	Intron 2 of 13	1		ENSP00000461421.1
MMP2	ENST00000568715.5	c.-76+67G>T		intron_variant	Intron 1 of 3	4		ENSP00000457949.1
MMP2	ENST00000219070.9	c.-448G>T		upstream_gene_variant		1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes AF: 0.0570 AC: 8079 AN: 141858 Hom.: 304 Cov.: 31

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00557

Gnomad AMR AF: 0.0937

Gnomad ASJ AF: 0.0913

Gnomad EAS AF: 0.00176

Gnomad SAS AF: 0.0594

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0733

Gnomad NFE AF: 0.0693

Gnomad OTH AF: 0.0640

GnomAD4 exome AF: 0.0379 AC: 35 AN: 924 Hom.: 2 Cov.: 0 AF XY: 0.0440 AC XY: 24 AN XY: 546

African (AFR) AF: 0.00 AC: 0 AN: 38

American (AMR) AF: 0.0357 AC: 1 AN: 28

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 1 AN: 46

East Asian (EAS) AF: 0.00 AC: 0 AN: 26

South Asian (SAS) AF: 0.00 AC: 0 AN: 8

European-Finnish (FIN) AF: 0.0263 AC: 1 AN: 38

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0439 AC: 29 AN: 660

Other (OTH) AF: 0.0385 AC: 3 AN: 78

GnomAD4 genome AF: 0.0570 AC: 8084 AN: 141940 Hom.: 306 Cov.: 31 AF XY: 0.0585 AC XY: 4004 AN XY: 68492

African (AFR) AF: 0.0129 AC: 493 AN: 38172

American (AMR) AF: 0.0940 AC: 1250 AN: 13298

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 310 AN: 3396

East Asian (EAS) AF: 0.00177 AC: 8 AN: 4532

South Asian (SAS) AF: 0.0595 AC: 261 AN: 4384

European-Finnish (FIN) AF: 0.116 AC: 1025 AN: 8854

Middle Eastern (MID) AF: 0.0750 AC: 21 AN: 280

European-Non Finnish (NFE) AF: 0.0693 AC: 4586 AN: 66162

Other (OTH) AF: 0.0636 AC: 125 AN: 1964

Alfa AF: 0.0489 Hom.: 78

Bravo AF: 0.0498

Asia WGS AF: 0.0240 AC: 85 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.80
PhyloP100		0.15
PromoterAI		-0.081	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17859829; hg19: chr16-55512944;