20-46011586-A-G

Variant names:

• chr20-46011586-A-G
• rs17576
• NM_004994.3:c.836A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004994.3(MMP9):​c.836A>G​(p.Gln279Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,613,158 control chromosomes in the GnomAD database, including 115,296 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10759 hom., cov: 31)
  • Exomes 𝑓: 0.37 (104537 hom.)
• Consequence: MMP9 NM_004994.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.23
• Publications: 369 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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• metaphyseal anadysplasia 2

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4534767E-6).
• BP6: Variant 20-46011586-A-G is Benign according to our data. Variant chr20-46011586-A-G is described in ClinVar as Benign. ClinVar VariationId is 338550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004994.3. 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
	MMP9	NM_004994.3	MANE Select	c.836A>G	p.Gln279Arg	missense	Exon 6 of 13	NP_004985.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	ENST00000372330.3	TSL:1 MANE Select	c.836A>G	p.Gln279Arg	missense	Exon 6 of 13	ENSP00000361405.3

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55636 AN: 151328 Hom.: 10757 Cov.: 31

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.727

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.358

GnomAD2 exomes AF: 0.389 AC: 97838 AN: 251348 AF XY: 0.399

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.745

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.371 AC: 542171 AN: 1461712 Hom.: 104537 Cov.: 61 AF XY: 0.375 AC XY: 272672 AN XY: 727162

African (AFR) AF: 0.351 AC: 11766 AN: 33480

American (AMR) AF: 0.229 AC: 10262 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 10306 AN: 26132

East Asian (EAS) AF: 0.696 AC: 27628 AN: 39700

South Asian (SAS) AF: 0.497 AC: 42867 AN: 86258

European-Finnish (FIN) AF: 0.407 AC: 21732 AN: 53384

Middle Eastern (MID) AF: 0.344 AC: 1982 AN: 5768

European-Non Finnish (NFE) AF: 0.353 AC: 392525 AN: 1111880

Other (OTH) AF: 0.383 AC: 23103 AN: 60394

GnomAD4 genome AF: 0.368 AC: 55669 AN: 151446 Hom.: 10759 Cov.: 31 AF XY: 0.375 AC XY: 27731 AN XY: 74018

African (AFR) AF: 0.345 AC: 14223 AN: 41280

American (AMR) AF: 0.274 AC: 4174 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1345 AN: 3458

East Asian (EAS) AF: 0.726 AC: 3694 AN: 5086

South Asian (SAS) AF: 0.519 AC: 2483 AN: 4786

European-Finnish (FIN) AF: 0.418 AC: 4397 AN: 10524

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.357 AC: 24194 AN: 67784

Other (OTH) AF: 0.359 AC: 752 AN: 2096

Alfa AF: 0.358 Hom.: 27606

Bravo AF: 0.355

TwinsUK AF: 0.355 AC: 1317

ALSPAC AF: 0.358 AC: 1381

ESP6500AA AF: 0.348 AC: 1533

ESP6500EA AF: 0.348 AC: 2991

ExAC AF: 0.392 AC: 47586

Asia WGS AF: 0.553 AC: 1920 AN: 3478

EpiCase AF: 0.350

EpiControl AF: 0.347

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20181264, 18455130, 20144500, 21844877, 19279308, 21655354, 16709939, 28453874, 21085059)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Metaphyseal anadysplasia 2 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.033
Sift	Benign	0.35	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.055
ClinPred		0.0035	T
GERP RS		2.7
Varity_R		0.073
gMVP		0.84
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17576; hg19: chr20-44640225; COSMIC: COSV63434086; COSMIC: COSV63434086;