20-46008772-CCACACACACACACACACACACACACACACACACA-CCACACACACACACACACACACACACA

Variant names:

• chr20-46008772-CCACACACA-C
• rs2234681
• NM_004994.3:c.-154_-147delCACACACA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_004994.3(MMP9):​c.-154_-147delCACACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 993,286 control chromosomes in the GnomAD database, including 104 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (44 hom., cov: 0)
  • Exomes 𝑓: 0.019 (60 hom.)
• Consequence: MMP9 NM_004994.3 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0847 is higher than 0.05.

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_-147delCACACACA		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_-147delCACACACA		upstream_gene	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.-154_-147delCACACACA		upstream_gene	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.-154_-147delCACACACA		upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 2949 AN: 141488 Hom.: 43 Cov.: 0

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.0928

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.0161

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0236

GnomAD4 exome AF: 0.0191 AC: 16274 AN: 851696 Hom.: 60 AF XY: 0.0211 AC XY: 9141 AN XY: 433774

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

African (AFR) AF: 0.0362 AC: 681 AN: 18814

American (AMR) AF: 0.0159 AC: 500 AN: 31474

Ashkenazi Jewish (ASJ) AF: 0.0252 AC: 490 AN: 19456

East Asian (EAS) AF: 0.0385 AC: 1067 AN: 27728

South Asian (SAS) AF: 0.0718 AC: 4530 AN: 63058

European-Finnish (FIN) AF: 0.0298 AC: 929 AN: 31200

Middle Eastern (MID) AF: 0.0220 AC: 65 AN: 2952

European-Non Finnish (NFE) AF: 0.0116 AC: 7180 AN: 618614

Other (OTH) AF: 0.0217 AC: 832 AN: 38400

⚠️ 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: 0.0208 AC: 2948 AN: 141590 Hom.: 44 Cov.: 0 AF XY: 0.0228 AC XY: 1559 AN XY: 68260

African (AFR) AF: 0.0219 AC: 815 AN: 37178

American (AMR) AF: 0.0192 AC: 274 AN: 14268

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 82 AN: 3394

East Asian (EAS) AF: 0.0184 AC: 80 AN: 4344

South Asian (SAS) AF: 0.0923 AC: 386 AN: 4184

European-Finnish (FIN) AF: 0.0327 AC: 302 AN: 9228

Middle Eastern (MID) AF: 0.0175 AC: 5 AN: 286

European-Non Finnish (NFE) AF: 0.0145 AC: 957 AN: 65884

Other (OTH) AF: 0.0239 AC: 46 AN: 1928

Alfa AF: 0.0129 Hom.: 555

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28

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;