Genetic Variant MMP9:p.Arg668Pro (chr20-46014472-GA-CT) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_Supporting

The NM_004994.3(MMP9):c.2003_2004delGAinsCT (p.Arg668Pro) variant causes a missense, splice region change. The gene MMP9 is a known oncogene (CancerMine: 1 TSG, 22 oncogene, 5 driver citations). The gene MMP9 is a cancer driver gene (CancerMine: 1 TSG, 22 oncogene, 5 driver citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R668E: Uncertain_significance (ClinVar VariationId 4752768, 1 star); p.R668G: Uncertain_significance (ClinVar VariationId 500498, 1 star); p.R668Q: Benign (ClinVar VariationId 338559, 2 stars)

Frequency

Genomes: not found (cov: 32)

Consequence

MMP9
NM_004994.3 missense, splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.62

Publications

0 publications found

Variant links:

Genes affected

MMP9 (HGNC:7176): (matrix metallopeptidase 9) Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades type IV and V collagens. Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling. [provided by RefSeq, Jul 2008]

MMP9 Gene-Disease associations (from GenCC):

metaphyseal anadysplasia 2
Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
metaphyseal anadysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MMP9 links:

SLC12A5-AS1 (HGNC:53143): ()

SLC12A5-AS1 links:

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new If you want to explore the variant's impact on the transcript NM_004994.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Show applied only (2)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer does not indicate an oncogenic effect; O6 not met via missense path; Splice-region variant — splicing algorithms predict an impact on splicing; supports O6

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004994.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MMP9 NM_004994.3	MANE Select	c.2003_2004delGAinsCT p.Arg668Pro	missensesplice_region	N/A	Prot: NP_004985.2 UniProt: P14780
	SLC12A5-AS1 NR_147699.1		n.984_985delTCinsAG	non_coding_transcript_exon	Exon 3 of 3	Prot:

MMP9 NM_004994.3

MANE Select

HGVSc / HGVSpc.2003_2004delGAinsCTp.Arg668Pro

Exon rankN/A

missensesplice_region

Prot: NP_004985.2UniProt: P14780

SLC12A5-AS1 NR_147699.1

HGVSc / HGVSpn.984_985delTCinsAG

Exon rankExon 3 of 3

non_coding_transcript_exon

Prot:

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
MMP9 ENST00000372330.3	TSL:1MANE Select	c.2003_2004delGAinsCT p.Arg668Pro	missensesplice_region	N/A	Prot: ENSP00000361405.3 UniProt: P14780
MMP9 ENST00000898203.1		c.1940_1941delGAinsCT p.Arg647Pro	missensesplice_region	N/A	Prot: ENSP00000568262.1 UniProt: A0ACI8QNM3
MMP9 ENST00000898204.1		c.1874_1875delGAinsCT p.Arg625Pro	missensesplice_region	N/A	Prot: ENSP00000568263.1 UniProt: A0ACI8QNM4

MMP9 ENST00000372330.3

TSL:1MANE Select

HGVSc / HGVSpc.2003_2004delGAinsCTp.Arg668Pro

Exon rankN/A

missensesplice_region

Prot: ENSP00000361405.3UniProt: P14780

MMP9 ENST00000898203.1

HGVSc / HGVSpc.1940_1941delGAinsCTp.Arg647Pro

Exon rankN/A

missensesplice_region

Prot: ENSP00000568262.1UniProt: A0ACI8QNM3

MMP9 ENST00000898204.1

HGVSc / HGVSpc.1874_1875delGAinsCTp.Arg625Pro

Exon rankN/A

missensesplice_region

Prot: ENSP00000568263.1UniProt: A0ACI8QNM4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.6

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence