20-46008772-C-CCACA

Variant names:

• chr20-46008772-C-CCACA
• rs2234681
• NM_004994.3:c.-155_-154insCACA

Variant summary

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

The NM_004994.3(MMP9):​c.-155_-154insCACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 996,250 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 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00052 (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 186 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_-154insCACA		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_-154insCACA		upstream_gene	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.-155_-154insCACA		upstream_gene	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.-155_-154insCACA		upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 186 AN: 141530 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.0167

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00207

Gnomad SAS AF: 0.000716

Gnomad FIN AF: 0.000325

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000910

Gnomad OTH AF: 0.00105

GnomAD4 exome AF: 0.000522 AC: 446 AN: 854618 Hom.: 0 AF XY: 0.000531 AC XY: 231 AN XY: 435276

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

African (AFR) AF: 0.000686 AC: 13 AN: 18946

American (AMR) AF: 0.000853 AC: 27 AN: 31640

Ashkenazi Jewish (ASJ) AF: 0.000102 AC: 2 AN: 19550

East Asian (EAS) AF: 0.00224 AC: 63 AN: 28156

South Asian (SAS) AF: 0.000866 AC: 55 AN: 63492

European-Finnish (FIN) AF: 0.000732 AC: 23 AN: 31404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2964

European-Non Finnish (NFE) AF: 0.000387 AC: 240 AN: 619918

Other (OTH) AF: 0.000597 AC: 23 AN: 38548

⚠️ 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: 0.00131 AC: 186 AN: 141632 Hom.: 0 Cov.: 0 AF XY: 0.00127 AC XY: 87 AN XY: 68288

African (AFR) AF: 0.00145 AC: 54 AN: 37194

American (AMR) AF: 0.00280 AC: 40 AN: 14268

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

East Asian (EAS) AF: 0.00207 AC: 9 AN: 4342

South Asian (SAS) AF: 0.000717 AC: 3 AN: 4186

European-Finnish (FIN) AF: 0.000325 AC: 3 AN: 9236

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

European-Non Finnish (NFE) AF: 0.000910 AC: 60 AN: 65902

Other (OTH) AF: 0.00104 AC: 2 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		-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;