20-46008772-CCACACACACACACACACACACACACACACACACA-CCACACACACACACACACACACACACACACACACACACACACACACA

Variant names:

• chr20-46008772-C-CCACACACACACA
• rs2234681
• NM_004994.3:c.-155_-154insCACACACACACA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004994.3(MMP9):​c.-155_-154insCACACACACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.000021 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000094 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Uncertain_significance. The variant received 0 ACMG points.

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_-154insCACACACACACA		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_-154insCACACACACACA		upstream_gene	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.-155_-154insCACACACACACA		upstream_gene	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.-155_-154insCACACACACACA		upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.0000212 AC: 3 AN: 141538 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000936 AC: 8 AN: 854886 Hom.: 0 AF XY: 0.00000689 AC XY: 3 AN XY: 435422

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

African (AFR) AF: 0.0000528 AC: 1 AN: 18950

American (AMR) AF: 0.00 AC: 0 AN: 31658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19556

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

South Asian (SAS) AF: 0.0000157 AC: 1 AN: 63514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31422

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

European-Non Finnish (NFE) AF: 0.00000968 AC: 6 AN: 620086

Other (OTH) AF: 0.00 AC: 0 AN: 38564

⚠️ 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: 0.0000212 AC: 3 AN: 141538 Hom.: 0 Cov.: 0 AF XY: 0.0000293 AC XY: 2 AN XY: 68180

African (AFR) AF: 0.0000539 AC: 2 AN: 37080

American (AMR) AF: 0.00 AC: 0 AN: 14252

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4358

South Asian (SAS) AF: 0.00 AC: 0 AN: 4192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65910

Other (OTH) AF: 0.00 AC: 0 AN: 1910

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;