Genetic Variant MMP9:c.-154_-141delCACACACACACACA (chr20-46008772-CCACACACACACACA-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004994.3(MMP9):c.-154_-141delCACACACACACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 996,364 control chromosomes in the GnomAD database, including 42 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 0)

Exomes 𝑓: 0.0016 ( 40 hom. )

Consequence

MMP9
NM_004994.3 upstream_gene

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.65

Publications

21 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 178 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP9	NM_004994.3 link	c.-154_-141delCACACACACACACA		upstream_gene_variant		ENST00000372330.3	NP_004985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP9	ENST00000372330.3 link	c.-154_-141delCACACACACACACA		upstream_gene_variant		1	NM_004994.3	ENSP00000361405.3

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

178

AN:

141536

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00382

Gnomad FIN

AF:

0.000325

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00164

Gnomad OTH

AF:

0.00157

GnomAD4 exome

AF:

0.00160

AC:

1366

AN:

854726

Hom.:

AF XY:

0.00163

AC XY:

711

AN XY:

435340

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

18948

American (AMR)

AF:

0.000505

AC:

AN:

31654

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

19556

East Asian (EAS)

AF:

0.000497

AC:

AN:

28168

South Asian (SAS)

AF:

0.00296

AC:

188

AN:

63506

European-Finnish (FIN)

AF:

0.000605

AC:

AN:

31420

Middle Eastern (MID)

AF:

0.000337

AC:

AN:

2964

European-Non Finnish (NFE)

AF:

0.00168

AC:

1043

AN:

619948

Other (OTH)

AF:

0.00132

AC:

AN:

38562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00126

AC:

178

AN:

141638

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

68294

show subpopulations

African (AFR)

AF:

0.00110

AC:

AN:

37198

American (AMR)

AF:

0.000491

AC:

AN:

14270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.00

AC:

AN:

4344

South Asian (SAS)

AF:

0.00382

AC:

AN:

4186

European-Finnish (FIN)

AF:

0.000325

AC:

AN:

9236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00164

AC:

108

AN:

65900

Other (OTH)

AF:

0.00156

AC:

AN:

1928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

555

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Splicing

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

Publications

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20-46008772-CCACACACACACACACACACACACACACACACACA-CCACACACACACACACACACA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over