20-46008772-CCACACACACACACACACACACACACACACACACA-CCACACACACACACACACACACACACACACACACACA

Variant names:

• chr20-46008772-C-CCA
• rs2234681
• NM_004994.3:c.-155_-154insCA

Variant summary

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

The NM_004994.3(MMP9):​c.-155_-154insCA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 994,712 control chromosomes in the GnomAD database, including 17 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 0)
  • Exomes 𝑓: 0.0060 (0 hom.)
• Consequence: MMP9 NM_004994.3 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.112
• 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 1869 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_-154insCA		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.-155_-154insCA		upstream_gene	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.-155_-154insCA		upstream_gene	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.-155_-154insCA		upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 1870 AN: 141448 Hom.: 17 Cov.: 0

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00670

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00943

GnomAD4 exome AF: 0.00596 AC: 5084 AN: 853162 Hom.: 0 AF XY: 0.00634 AC XY: 2754 AN XY: 434454

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

African (AFR) AF: 0.00713 AC: 135 AN: 18922

American (AMR) AF: 0.0132 AC: 417 AN: 31548

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 214 AN: 19452

East Asian (EAS) AF: 0.0136 AC: 383 AN: 28098

South Asian (SAS) AF: 0.0112 AC: 711 AN: 63286

European-Finnish (FIN) AF: 0.0103 AC: 324 AN: 31324

Middle Eastern (MID) AF: 0.00710 AC: 21 AN: 2958

European-Non Finnish (NFE) AF: 0.00425 AC: 2631 AN: 619132

Other (OTH) AF: 0.00645 AC: 248 AN: 38442

⚠️ 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: 0.0132 AC: 1869 AN: 141550 Hom.: 17 Cov.: 0 AF XY: 0.0129 AC XY: 882 AN XY: 68246

African (AFR) AF: 0.0123 AC: 459 AN: 37182

American (AMR) AF: 0.0156 AC: 222 AN: 14260

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 84 AN: 3392

East Asian (EAS) AF: 0.0168 AC: 73 AN: 4344

South Asian (SAS) AF: 0.0160 AC: 67 AN: 4184

European-Finnish (FIN) AF: 0.0141 AC: 130 AN: 9216

Middle Eastern (MID) AF: 0.00699 AC: 2 AN: 286

European-Non Finnish (NFE) AF: 0.0123 AC: 808 AN: 65864

Other (OTH) AF: 0.00935 AC: 18 AN: 1926

Alfa AF: 0.0125 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

Other links and lift over

dbSNP: rs2234681; hg19: chr20-44637411;