chr20-46008772-CCACACACACACA-C

Variant names:

• chr20-46008772-CCACACACACACA-C
• rs2234681
• NM_004994.3:c.-154_-143delCACACACACACA

Variant summary

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

The NM_004994.3(MMP9):​c.-154_-143delCACACACACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000839 in 996,380 control chromosomes in the GnomAD database, including 1 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 0.0012 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00079 (1 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 165 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	NM_004994.3	MANE Select	c.-154_-143delCACACACACACA		upstream_gene	N/A	NP_004985.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	ENST00000372330.3	TSL:1 MANE Select	c.-154_-143delCACACACACACA		upstream_gene	N/A	ENSP00000361405.3

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 165 AN: 141534 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000688

Gnomad SAS AF: 0.00262

Gnomad FIN AF: 0.000108

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000379

Gnomad OTH AF: 0.00157

GnomAD4 exome AF: 0.000785 AC: 671 AN: 854744 Hom.: 1 AF XY: 0.000836 AC XY: 364 AN XY: 435332

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

African (AFR) AF: 0.00613 AC: 116 AN: 18936

American (AMR) AF: 0.00180 AC: 57 AN: 31652

Ashkenazi Jewish (ASJ) AF: 0.000205 AC: 4 AN: 19554

East Asian (EAS) AF: 0.00124 AC: 35 AN: 28150

South Asian (SAS) AF: 0.00299 AC: 190 AN: 63474

European-Finnish (FIN) AF: 0.000255 AC: 8 AN: 31412

Middle Eastern (MID) AF: 0.00135 AC: 4 AN: 2964

European-Non Finnish (NFE) AF: 0.000342 AC: 212 AN: 620046

Other (OTH) AF: 0.00117 AC: 45 AN: 38556

⚠️ 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: 0.00116 AC: 165 AN: 141636 Hom.: 0 Cov.: 0 AF XY: 0.00127 AC XY: 87 AN XY: 68294

African (AFR) AF: 0.00288 AC: 107 AN: 37194

American (AMR) AF: 0.000981 AC: 14 AN: 14270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.000691 AC: 3 AN: 4344

South Asian (SAS) AF: 0.00263 AC: 11 AN: 4186

European-Finnish (FIN) AF: 0.000108 AC: 1 AN: 9236

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.000379 AC: 25 AN: 65902

Other (OTH) AF: 0.00156 AC: 3 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;