NM_004994.3:c.2003G>A

Variant names:

• chr20-46014472-G-A
• rs17577
• NM_004994.3:c.2003G>A
• MMP9 p.Arg668Gln

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

The NM_004994.3(MMP9):c.2003G>A (p.Arg668Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.153 (AC=237,425) in the gnomAD database across 1,549,446 control chromosomes, including 19,464 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.287. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). 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) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.16 (1940 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17524 hom.)
• Consequence: MMP9 NM_004994.3 missense, splice_region
• Scores: Splicing: ADA: 0.00001114
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.190
• Publications: 1 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: Benign. The variant received -14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2866 — exceeds 5%% threshold (BA1 applied)

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.2003G>A p.Arg668Gln	missensesplice_region	Exon 12 of 13	Prot: NP_004985.2 UniProt:
	SLC12A5-AS1 NR_147699.1		n.985C>T	non_coding_transcript_exon	Exon 3 of 3	Prot:

MMP9 NM_004994.3

MANE Select

HGVSc / HGVSpc.2003G>Ap.Arg668Gln

Exon rankExon 12 of 13

missensesplice_region

Prot: NP_004985.2UniProt: P14780

SLC12A5-AS1 NR_147699.1

HGVSc / HGVSpn.985C>T

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.2003G>A p.Arg668Gln	missensesplice_region	Exon 12 of 13	Prot: ENSP00000361405.3 UniProt:
	MMP9 ENST00000898203.1		c.1940G>A p.Arg647Gln	missensesplice_region	Exon 12 of 13	Prot: ENSP00000568262.1 UniProt:
	MMP9 ENST00000898204.1		c.1874G>A p.Arg625Gln	missensesplice_region	Exon 11 of 12	Prot: ENSP00000568263.1 UniProt:

MMP9 ENST00000372330.3

TSL:1MANE Select

HGVSc / HGVSpc.2003G>Ap.Arg668Gln

Exon rankExon 12 of 13

missensesplice_region

Prot: ENSP00000361405.3UniProt: P14780

MMP9 ENST00000898203.1

HGVSc / HGVSpc.1940G>Ap.Arg647Gln

Exon rankExon 12 of 13

missensesplice_region

Prot: ENSP00000568262.1UniProt: A0ACI8QNM3

MMP9 ENST00000898204.1

HGVSc / HGVSpc.1874G>Ap.Arg625Gln

Exon rankExon 11 of 12

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.156	AC:23790	Hom:1942	AN:152078	Cov:32
GnomAD2 exomes	AF: 0.159	AC:24487	Hom:	AN:154326	Cov:
GnomAD4 exome	AF: 0.153	AC:213619	Hom:17524	AN:1397250	Cov:35
GnomAD4 genome	AF: 0.156	AC:23806	Hom:1940	AN:152196	Cov:32
TOPMed (Bravo)	AF: 0.149	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.147	AC:95680	Hom:7214	AN:652498	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.130	AC:304	Hom:22	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.126	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.100	AC:30	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.131	AC:1474	Hom:	AN:11216	Cov:
GenomeAsia100K	AF: 0.210	AC:728	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.132	AC:952	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.151	AC:284	Hom:	AN:1882	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.191	AC:23455	Hom:2295	AN:122610	Cov:
Turkish Variome	AF: 0.170	AC:1123	Hom:103	AN:6606	Cov:
UK10K	AF: 0.142	AC:1076	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.128	AC:1149	Hom:74	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.142 *	1364	9616	0.134 *	1395	10420
BipEx(Bipolar disorder (including schizoaffective))	0.149	4226	28420	0.142	4100	28844
Epi25(Epilepsy)	0.150	6283	41958	0.146	9787	66886
SCHEMA(Schizophrenia)	0.195	25023	128164	0.192	38271	198908

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Metaphyseal anadysplasia 2 (2)
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	3.8
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.048	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.039	N
FuncVEP CTI	Benign	0.0031
GPN-Star LLR	N/A	1.6
GPN-Star score	N/A	0.70
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.94	T
Mutation Taster	N/A	94/6	polymorphism (auto)
MutationAssessor	Benign	0.33	N
PhyloP100	Benign	0.19
popEVE	Benign	-2.9
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.075
Sift	Benign	1.0	T
Sift4G	Benign	0.65	T
Varity_R	N/A	0.071
VESM-3B	Benign	-4.9

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

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

dbSNP: rs17577;

hg19: chr20-44643111;

COSMIC: COSV63433825;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar