chr20-46008772-CCACACACACACACACACACACA-C

Variant names:

• chr20-46008772-CCACACACACACACACACACACA-C
• rs2234681
• NM_004994.3:c.-154_-133delCACACACACACACACACACACA

Variant summary

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

The NM_004994.3(MMP9):​c.-154_-133delCACACACACACACACACACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 990,842 control chromosomes in the GnomAD database, including 4 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 0.000099 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: MMP9 NM_004994.3 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65
• Publications: 21 publications found

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)

ACMG classification

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

• BS2: High AC in GnomAd4 at 14 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.-154_-133delCACACACACACACACACACACA		upstream_gene	N/A	NP_004985.2	P14780

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	ENST00000372330.3	TSL:1 MANE Select	c.-154_-133delCACACACACACACACACACACA		upstream_gene	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.-154_-133delCACACACACACACACACACACA		upstream_gene	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.-154_-133delCACACACACACACACACACACA		upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.0000989 AC: 14 AN: 141532 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000702

Gnomad ASJ AF: 0.000589

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00131 AC: 1113 AN: 849208 Hom.: 4 AF XY: 0.00134 AC XY: 581 AN XY: 432482

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

African (AFR) AF: 0.000846 AC: 16 AN: 18916

American (AMR) AF: 0.000475 AC: 15 AN: 31582

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 32 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 28172

South Asian (SAS) AF: 0.000426 AC: 27 AN: 63384

European-Finnish (FIN) AF: 0.00106 AC: 33 AN: 31100

Middle Eastern (MID) AF: 0.00204 AC: 6 AN: 2934

European-Non Finnish (NFE) AF: 0.00150 AC: 922 AN: 615494

Other (OTH) AF: 0.00162 AC: 62 AN: 38252

⚠️ 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.

GnomAD4 genome AF: 0.0000988 AC: 14 AN: 141634 Hom.: 0 Cov.: 0 AF XY: 0.0000732 AC XY: 5 AN XY: 68292

African (AFR) AF: 0.0000269 AC: 1 AN: 37198

American (AMR) AF: 0.0000701 AC: 1 AN: 14268

Ashkenazi Jewish (ASJ) AF: 0.000589 AC: 2 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 4344

South Asian (SAS) AF: 0.00 AC: 0 AN: 4186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000152 AC: 10 AN: 65900

Other (OTH) AF: 0.00 AC: 0 AN: 1928

Alfa AF: 0.00 Hom.: 555

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

Splicing

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

Other links and lift over

dbSNP: rs2234681; hg19: chr20-44637411;