Genetic Variant NM_004994.3:c.-155_-154insCACACA (chr20-46008772-C-CCACACA) – 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.-155_-154insCACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 996,438 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 0.00070 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00027 ( 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:

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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 99 Unknown,AD gene.

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_-154insCACACA		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_-154insCACACA	upstream_gene	N/A	ENSP00000361405.3	P14780
MMP9	ENST00000898203.1		c.-155_-154insCACACA	upstream_gene	N/A	ENSP00000568262.1
MMP9	ENST00000898204.1		c.-155_-154insCACACA	upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes

AF:

0.000699

AC:

AN:

141536

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000728

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000351

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00161

Gnomad SAS

AF:

0.000239

Gnomad FIN

AF:

0.000325

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000819

Gnomad OTH

AF:

0.00105

GnomAD4 exome

AF:

0.000271

AC:

232

AN:

854800

Hom.:

AF XY:

0.000289

AC XY:

126

AN XY:

435382

show subpopulations

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

African (AFR)

AF:

0.000158

AC:

AN:

18950

American (AMR)

AF:

0.000253

AC:

AN:

31654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19556

East Asian (EAS)

AF:

0.000887

AC:

AN:

28172

South Asian (SAS)

AF:

0.000142

AC:

AN:

63516

European-Finnish (FIN)

AF:

0.000446

AC:

AN:

31418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2962

European-Non Finnish (NFE)

AF:

0.000263

AC:

163

AN:

620012

Other (OTH)

AF:

0.000259

AC:

AN:

38560

⚠️ 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: 0.322

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:

0.000699

AC:

AN:

141638

Hom.:

Cov.:

AF XY:

0.000586

AC XY:

AN XY:

68294

show subpopulations

African (AFR)

AF:

0.000726

AC:

AN:

37196

American (AMR)

AF:

0.000350

AC:

AN:

14270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.00161

AC:

AN:

4344

South Asian (SAS)

AF:

0.000239

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:

0.000819

AC:

AN:

65902

Other (OTH)

AF:

0.00104

AC:

AN:

1928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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