chr20-46014472-G-A

Variant names:

Variant summary

Our verdict is 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

164 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 and MMP9 antisense RNA 1)

SLC12A5-AS1 links:

Genome browser will be placed here

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 ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

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	missense splice_region	Exon 12 of 13	NP_004985.2	P14780
	SLC12A5-AS1	NR_147699.1		n.985C>T		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMP9	ENST00000372330.3	TSL:1 MANE Select	c.2003G>A	p.Arg668Gln	missense splice_region	Exon 12 of 13	ENSP00000361405.3	P14780
MMP9	ENST00000898203.1		c.1940G>A	p.Arg647Gln	missense splice_region	Exon 12 of 13	ENSP00000568262.1	A0ACI8QNM3
MMP9	ENST00000898204.1		c.1874G>A	p.Arg625Gln	missense splice_region	Exon 11 of 12	ENSP00000568263.1	A0ACI8QNM4

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23790

AN:

152078

Hom.:

1942

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.0940

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.170

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.152

GnomAD2 exomes

AF:

0.159

AC:

24487

AN:

154326

AF XY:

0.169

show subpopulations

Gnomad AFR exome

AF:

0.177

Gnomad AMR exome

AF:

0.0695

Gnomad ASJ exome

AF:

0.161

Gnomad EAS exome

AF:

0.127

Gnomad FIN exome

AF:

0.169

Gnomad NFE exome

AF:

0.144

Gnomad OTH exome

AF:

0.161

GnomAD4 exome

AF:

0.153

AC:

213619

AN:

1397250

Hom.:

17524

Cov.:

AF XY:

0.157

AC XY:

108526

AN XY:

689314

show subpopulations

African (AFR)

AF:

0.181

AC:

5718

AN:

31590

American (AMR)

AF:

0.0745

AC:

2661

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

4005

AN:

25182

East Asian (EAS)

AF:

0.164

AC:

5856

AN:

35736

South Asian (SAS)

AF:

0.290

AC:

22953

AN:

79222

European-Finnish (FIN)

AF:

0.164

AC:

7794

AN:

47526

Middle Eastern (MID)

AF:

0.155

AC:

881

AN:

5694

European-Non Finnish (NFE)

AF:

0.143

AC:

154329

AN:

1078608

Other (OTH)

AF:

0.162

AC:

9422

AN:

57988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

9887

19773

29660

39546

49433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5656

11312

16968

22624

28280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.156

AC:

23806

AN:

152196

Hom.:

1940

Cov.:

AF XY:

0.158

AC XY:

11759

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.177

AC:

7331

AN:

41524

American (AMR)

AF:

0.0938

AC:

1435

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

546

AN:

3470

East Asian (EAS)

AF:

0.148

AC:

765

AN:

5174

South Asian (SAS)

AF:

0.298

AC:

1438

AN:

4820

European-Finnish (FIN)

AF:

0.170

AC:

1806

AN:

10596

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.148

AC:

10042

AN:

67988

Other (OTH)

AF:

0.156

AC:

329

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1069

2137

3206

4274

5343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.149

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.147

AC:

95680

AN:

652498

Hom.:

7214

Local populations

ABraOM SABE-WGS-1171

AF:

0.130

AC:

304

AN:

2342

Hom.:

ChinaMAP Phase 1

AF:

0.126

Denmark Genome

AF:

0.100

AC:

AN:

300

ESP6500 (Exome Variant Server)

AF:

0.131

AC:

1474

AN:

11216

show subpopulations

European American

AF:

0.117

AC:

860

AN:

7362

African American

AF:

0.159

AC:

614

AN:

3854

GenomeAsia100K

AF:

0.210

AC:

728

AN:

3478

show subpopulations

Oceania

AF:

0.115

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.121

AC:

AN:

702

Hom.:

South-East Asia

AF:

0.168

AC:

116

AN:

692

Hom.:

South Asia

AF:

0.307

AC:

444

AN:

1448

Hom.:

Africa

AF:

0.135

AC:

AN:

208

Hom.:

America

AF:

0.00

AC:

AN:

Hom.:

West Eurasia

AF:

0.167

AC:

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.132

AC:

952

AN:

7234

Qatari Genome

AF:

0.151

AC:

284

AN:

1882

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.191

AC:

23455

AN:

122610

Hom.:

2295

Turkish Variome

AF:

0.170

AC:

1123

AN:

6606

Hom.:

103

UK10K

AF:

0.142

AC:

1076

AN:

7562

show subpopulations

TwinsUK

AF:

0.138

AC:

493

AN:

3574

ALSPAC

AF:

0.147

AC:

565

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.128

AC:

1149

AN:

8960

Hom.:

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

1364 / 9616AF: 0.141847

1395 / 10420AF: 0.133877

BipEx

(Bipolar disorder (including schizoaffective))

4226 / 28420AF: 0.148698

4100 / 28844AF: 0.142144

Epi25

(Epilepsy)

6283 / 41958AF: 0.149745

9787 / 66886AF: 0.146324

SCHEMA

(Schizophrenia)

25023 / 128164AF: 0.195242

38271 / 198908AF: 0.192406

Allele 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

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Metaphyseal anadysplasia 2 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.048

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.33

PhyloP100

0.19

PrimateAI

Benign

0.20

PROVEAN

Benign

0.30

REVEL

Benign

0.075

Sift

Benign

1.0

Sift4G

Benign

0.65

Varity_R

0.071

popEVE

Benign

-2.9

(source)

VESM-3B

Benign

-4.9

(source)

FuncVEP CTI

Benign

0.0031

(source)

AlphaGenome AVI

Benign

3.8

(source)

GPN-Star LLR

1.6

(source)

GPN-Star score

0.70

(source)

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.0

(source)

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.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over