20-46014472-G-C

Variant names:

• chr20-46014472-G-C
• rs17577
• NM_004994.3:c.2003G>C
• MMP9 p.Arg668Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4

The NM_004994.3(MMP9):c.2003G>C (p.Arg668Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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: Splicing: ADA: 0.000003855
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 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.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

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>C p.Arg668Pro	missensesplice_region	Exon 12 of 13	Prot: NP_004985.2 UniProt:
	SLC12A5-AS1 NR_147699.1		n.985C>G	non_coding_transcript_exon	Exon 3 of 3	Prot:

MMP9 NM_004994.3

MANE Select

HGVSc / HGVSpc.2003G>Cp.Arg668Pro

Exon rankExon 12 of 13

missensesplice_region

Prot: NP_004985.2UniProt: P14780

SLC12A5-AS1 NR_147699.1

HGVSc / HGVSpn.985C>G

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>C p.Arg668Pro	missensesplice_region	Exon 12 of 13	Prot: ENSP00000361405.3 UniProt:
	MMP9 ENST00000898203.1		c.1940G>C p.Arg647Pro	missensesplice_region	Exon 12 of 13	Prot: ENSP00000568262.1 UniProt:
	MMP9 ENST00000898204.1		c.1874G>C p.Arg625Pro	missensesplice_region	Exon 11 of 12	Prot: ENSP00000568263.1 UniProt:

MMP9 ENST00000372330.3

TSL:1MANE Select

HGVSc / HGVSpc.2003G>Cp.Arg668Pro

Exon rankExon 12 of 13

missensesplice_region

Prot: ENSP00000361405.3UniProt: P14780

MMP9 ENST00000898203.1

HGVSc / HGVSpc.1940G>Cp.Arg647Pro

Exon rankExon 12 of 13

missensesplice_region

Prot: ENSP00000568262.1UniProt: A0ACI8QNM3

MMP9 ENST00000898204.1

HGVSc / HGVSpc.1874G>Cp.Arg625Pro

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.39	N
FuncVEP CTI	Pathogenic	0.55
GPN-Star LLR	N/A	-5.6
GPN-Star score	N/A	5.6
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	65/35	polymorphism
MutationAssessor	Uncertain	2.1	M
PhyloP100	Benign	0.19
popEVE	Benign	-3.2
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Benign	0.086	T
Sift4G	Benign	0.21	T
Varity_R	N/A	0.57
VESM-3B	Benign	-12

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.0000039
dbscSNV1_RF	Benign	0.11
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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar