16-55505842-G-A

Variant names:

• chr16-55505842-G-A
• rs17860021
• NM_004530.6:c.*400G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000219070.9(MMP2):​c.*400G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 291,320 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: MMP2 ENST00000219070.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.42
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-55505842-G-A is Benign according to our data. Variant chr16-55505842-G-A is described in ClinVar as Benign. ClinVar VariationId is 319777.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00114 (173/152334) while in subpopulation EAS AF = 0.0251 (130/5174). AF 95% confidence interval is 0.0216. There are 6 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000219070.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	NM_004530.6	MANE Select	c.*400G>A		3_prime_UTR	Exon 13 of 13	NP_004521.1
	MMP2	NM_001127891.3		c.*400G>A		3_prime_UTR	Exon 13 of 13	NP_001121363.1
	MMP2	NM_001302508.1		c.*400G>A		3_prime_UTR	Exon 13 of 13	NP_001289437.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	ENST00000219070.9	TSL:1 MANE Select	c.*400G>A		3_prime_UTR	Exon 13 of 13	ENSP00000219070.4
	MMP2	ENST00000570308.5	TSL:1	c.*400G>A		3_prime_UTR	Exon 14 of 14	ENSP00000461421.1
	MMP2	ENST00000566564.1	TSL:3	n.*138-160G>A		intron	N/A	ENSP00000461915.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152216 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0251

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00117 AC: 163 AN: 138986 Hom.: 0 Cov.: 0 AF XY: 0.00117 AC XY: 86 AN XY: 73478

African (AFR) AF: 0.000430 AC: 2 AN: 4654

American (AMR) AF: 0.000159 AC: 1 AN: 6274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3630

East Asian (EAS) AF: 0.0211 AC: 148 AN: 7008

South Asian (SAS) AF: 0.0000945 AC: 2 AN: 21154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 520

European-Non Finnish (NFE) AF: 0.0000123 AC: 1 AN: 81234

Other (OTH) AF: 0.00123 AC: 9 AN: 7302

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152334 Hom.: 6 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74490

African (AFR) AF: 0.000746 AC: 31 AN: 41582

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0251 AC: 130 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000494 Hom.: 0

Bravo AF: 0.00143

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

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	-0.88
CADD	Benign	0.52
DANN	Benign	0.49
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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: rs17860021; hg19: chr16-55539754;