20-46008985-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004994.3(MMP9):c.59C>T(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,613,788 control chromosomes in the GnomAD database, including 1,152 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A20T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 172 hom., cov: 31)

Exomes 𝑓: 0.026 ( 980 hom. )

Consequence

MMP9
NM_004994.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.15

Publications

34 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
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
metaphyseal anadysplasia 2
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

MMP9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0017846525).

BP6

Variant 20-46008985-C-T is Benign according to our data. Variant chr20-46008985-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 338546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.114 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	NM_004994.3	MANE Select	c.59C>T	p.Ala20Val	missense	Exon 1 of 13	NP_004985.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MMP9	ENST00000372330.3	TSL:1 MANE Select	c.59C>T	p.Ala20Val	missense	Exon 1 of 13	ENSP00000361405.3
MMP9	ENST00000898203.1		c.59C>T	p.Ala20Val	missense	Exon 1 of 13	ENSP00000568262.1
MMP9	ENST00000898204.1		c.59C>T	p.Ala20Val	missense	Exon 1 of 12	ENSP00000568263.1

Frequencies

GnomAD3 genomes

AF:

0.0287

AC:

4357

AN:

152050

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00763

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.0541

Gnomad EAS

AF:

0.0304

Gnomad SAS

AF:

0.0244

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0210

Gnomad OTH

AF:

0.0320

GnomAD2 exomes

AF:

0.0408

AC:

10234

AN:

250604

AF XY:

0.0365

show subpopulations

Gnomad AFR exome

AF:

0.00581

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.0513

Gnomad EAS exome

AF:

0.0308

Gnomad FIN exome

AF:

0.0216

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0394

GnomAD4 exome

AF:

0.0262

AC:

38315

AN:

1461620

Hom.:

980

Cov.:

AF XY:

0.0259

AC XY:

18822

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.00493

AC:

165

AN:

33476

American (AMR)

AF:

0.151

AC:

6731

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0534

AC:

1396

AN:

26134

East Asian (EAS)

AF:

0.0398

AC:

1580

AN:

39690

South Asian (SAS)

AF:

0.0279

AC:

2402

AN:

86220

European-Finnish (FIN)

AF:

0.0193

AC:

1031

AN:

53376

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0208

AC:

23143

AN:

1111906

Other (OTH)

AF:

0.0294

AC:

1775

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

2428

4857

7285

9714

12142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

990

1980

2970

3960

4950

<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:

0.0287

AC:

4363

AN:

152168

Hom.:

172

Cov.:

AF XY:

0.0307

AC XY:

2286

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.00761

AC:

316

AN:

41524

American (AMR)

AF:

0.119

AC:

1815

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0541

AC:

188

AN:

3472

East Asian (EAS)

AF:

0.0303

AC:

156

AN:

5156

South Asian (SAS)

AF:

0.0249

AC:

120

AN:

4824

European-Finnish (FIN)

AF:

0.0184

AC:

195

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0210

AC:

1426

AN:

67994

Other (OTH)

AF:

0.0322

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

197

394

590

787

984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0186

Hom.:

Bravo

AF:

0.0352

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0210

AC:

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0223

AC:

192

ExAC

AF:

0.0344

AC:

4174

Asia WGS

AF:

0.0290

AC:

100

AN:

3478

EpiCase

AF:

0.0216

EpiControl

AF:

0.0227

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Metaphyseal anadysplasia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

2.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.76

REVEL

Benign

0.053

Sift

Benign

0.22

Sift4G

Benign

0.53

Polyphen

0.35

Vest4

0.087

ClinPred

0.0085

GERP RS

2.6

PromoterAI

-0.0038

Neutral

(source)

Varity_R

0.038

gMVP

0.51

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over