Genetic Variant MMP9:c.-155_-154insCACACACACA (chr20-46008772-C-CCACACACACA) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_004994.3(MMP9):c.-155_-154insCACACACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 996,520 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MMP9
NM_004994.3 upstream_gene

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.112

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS2

High AC in GnomAd4 at 12 Unknown,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.-155_-154insCACACACACA		upstream_gene	N/A	NP_004985.2	P14780

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MMP9	ENST00000372330.3	TSL:1 MANE Select	c.-155_-154insCACACACACA	upstream_gene	N/A	ENSP00000361405.3	P14780
MMP9	ENST00000898203.1		c.-155_-154insCACACACACA	upstream_gene	N/A	ENSP00000568262.1
MMP9	ENST00000898204.1		c.-155_-154insCACACACACA	upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes

AF:

0.0000848

AC:

AN:

141538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000459

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000433

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000910

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000187

AC:

AN:

854880

Hom.:

AF XY:

0.0000207

AC XY:

AN XY:

435414

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000528

AC:

AN:

18950

American (AMR)

AF:

0.0000632

AC:

AN:

31658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19556

East Asian (EAS)

AF:

0.000177

AC:

AN:

28172

South Asian (SAS)

AF:

0.00

AC:

AN:

63516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2964

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

620082

Other (OTH)

AF:

0.00

AC:

AN:

38562

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.294

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000847

AC:

AN:

141640

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

68294

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37198

American (AMR)

AF:

0.00

AC:

AN:

14270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.000460

AC:

AN:

4344

South Asian (SAS)

AF:

0.00

AC:

AN:

4186

European-Finnish (FIN)

AF:

0.000433

AC:

AN:

9236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000910

AC:

AN:

65902

Other (OTH)

AF:

0.00

AC:

AN:

1928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.11

Splicing

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