20-46008772-CCACACACACACACACACACACACACACACACACA-CCACACACACACACA

Variant names:

• chr20-46008772-CCACACACACACACACACACA-C
• rs2234681
• NM_004994.3:c.-154_-135delCACACACACACACACACACA

Variant summary

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

The NM_004994.3(MMP9):​c.-154_-135delCACACACACACACACACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 948,762 control chromosomes in the GnomAD database, including 240 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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 0)
  • Exomes 𝑓: 0.057 (240 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	NM_004994.3	MANE Select	c.-154_-135delCACACACACACACACACACA		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_-135delCACACACACACACACACACA		upstream_gene	N/A	ENSP00000361405.3

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 64 AN: 141280 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000211

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000593

Gnomad OTH AF: 0.000524

GnomAD4 exome AF: 0.0572 AC: 46196 AN: 807384 Hom.: 240 AF XY: 0.0573 AC XY: 23529 AN XY: 410928

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

African (AFR) AF: 0.0177 AC: 329 AN: 18610

American (AMR) AF: 0.0225 AC: 693 AN: 30780

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 1230 AN: 18300

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

South Asian (SAS) AF: 0.0275 AC: 1662 AN: 60466

European-Finnish (FIN) AF: 0.0658 AC: 1888 AN: 28690

Middle Eastern (MID) AF: 0.0695 AC: 190 AN: 2734

European-Non Finnish (NFE) AF: 0.0652 AC: 38053 AN: 583454

Other (OTH) AF: 0.0595 AC: 2151 AN: 36178

⚠️ 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: 0.000453 AC: 64 AN: 141378 Hom.: 0 Cov.: 0 AF XY: 0.000514 AC XY: 35 AN XY: 68140

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

African (AFR) AF: 0.000161 AC: 6 AN: 37188

American (AMR) AF: 0.000210 AC: 3 AN: 14256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4344

South Asian (SAS) AF: 0.00 AC: 0 AN: 4180

European-Finnish (FIN) AF: 0.00164 AC: 15 AN: 9126

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

European-Non Finnish (NFE) AF: 0.000593 AC: 39 AN: 65782

Other (OTH) AF: 0.000519 AC: 1 AN: 1926

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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;