NM_004994.3:c.2003_2004delGAinsCG

Variant names:

• chr20-46014472-GA-CG
• NM_004994.3:c.2003_2004delGAinsCG
• MMP9 p.Arg668Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_004994.3(MMP9):c.2003_2004delGAinsCG (p.Arg668Pro) variant causes a missense, splice region change. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62
• Publications: 0 publications found

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

SLC12A5-AS1 (HGNC:53143): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

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_2004delGAinsCG p.Arg668Pro	missensesplice_region	N/A	Prot: NP_004985.2 UniProt:
	SLC12A5-AS1 NR_147699.1		n.984_985delTCinsCG	non_coding_transcript_exon	Exon 3 of 3	Prot:

MMP9 NM_004994.3

MANE Select

HGVSc / HGVSpc.2003_2004delGAinsCGp.Arg668Pro

Exon rankN/A

missensesplice_region

Prot: NP_004985.2UniProt: P14780

SLC12A5-AS1 NR_147699.1

HGVSc / HGVSpn.984_985delTCinsCG

Exon rankExon 3 of 3

non_coding_transcript_exon

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MMP9 ENST00000372330.3	TSL:1MANE Select	c.2003_2004delGAinsCG p.Arg668Pro	missensesplice_region	N/A	Prot: ENSP00000361405.3 UniProt:
	MMP9 ENST00000898203.1		c.1940_1941delGAinsCG p.Arg647Pro	missensesplice_region	N/A	Prot: ENSP00000568262.1 UniProt:
	MMP9 ENST00000898204.1		c.1874_1875delGAinsCG p.Arg625Pro	missensesplice_region	N/A	Prot: ENSP00000568263.1 UniProt:

MMP9 ENST00000372330.3

TSL:1MANE Select

HGVSc / HGVSpc.2003_2004delGAinsCGp.Arg668Pro

Exon rankN/A

missensesplice_region

Prot: ENSP00000361405.3UniProt: P14780

MMP9 ENST00000898203.1

HGVSc / HGVSpc.1940_1941delGAinsCGp.Arg647Pro

Exon rankN/A

missensesplice_region

Prot: ENSP00000568262.1UniProt: A0ACI8QNM3

MMP9 ENST00000898204.1

HGVSc / HGVSpc.1874_1875delGAinsCGp.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.

Other links and lift over

hg19: chr20-44643111;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar