rs243834

chr16-55502775-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004530.6(MMP2):c.1770-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,611,146 control chromosomes in the GnomAD database, including 185,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15862 hom., cov: 32)
  • Exomes 𝑓: 0.48 (169406 hom.)
• Consequence: MMP2 NM_004530.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007448
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0560

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-55502775-A-G is Benign according to our data. Variant chr16-55502775-A-G is described in ClinVar as [Benign]. Clinvar id is 319766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-55502775-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP2	NM_004530.6	c.1770-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000219070.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP2	ENST00000219070.9	c.1770-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004530.6	P1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68923 AN: 151824 Hom.: 15857 Cov.: 32

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.450

GnomAD3 exomes AF: 0.487 AC: 122368 AN: 251062 Hom.: 30221 AF XY: 0.489 AC XY: 66284 AN XY: 135674

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.481

Gnomad ASJ exome AF: 0.446

Gnomad EAS exome AF: 0.635

Gnomad SAS exome AF: 0.518

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.480 AC: 700877 AN: 1459206 Hom.: 169406 Cov.: 31 AF XY: 0.481 AC XY: 349122 AN XY: 726050

Gnomad4 AFR exome AF: 0.380

Gnomad4 AMR exome AF: 0.479

Gnomad4 ASJ exome AF: 0.449

Gnomad4 EAS exome AF: 0.629

Gnomad4 SAS exome AF: 0.517

Gnomad4 FIN exome AF: 0.516

Gnomad4 NFE exome AF: 0.475

Gnomad4 OTH exome AF: 0.474

GnomAD4 genome AF: 0.454 AC: 68947 AN: 151940 Hom.: 15862 Cov.: 32 AF XY: 0.458 AC XY: 33978 AN XY: 74266

Gnomad4 AFR AF: 0.384

Gnomad4 AMR AF: 0.451

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.530

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.470

Gnomad4 OTH AF: 0.447

Alfa AF: 0.464 Hom.: 27226

Bravo AF: 0.446

Asia WGS AF: 0.550 AC: 1916 AN: 3478

EpiCase AF: 0.469

EpiControl AF: 0.469

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multicentric osteolysis nodulosis arthropathy spectrum Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	8.2
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.0080
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

Publications

LitVar

Other links and lift over

dbSNP: rs243834; hg19: chr16-55536687; COSMIC: COSV54599748; COSMIC: COSV54599748;