20-46008772-CCACACACACACACACACACACACACACACACACA-CCACACACACACACACACA

Variant names:

• chr20-46008772-CCACACACACACACACA-C
• rs2234681
• NM_004994.3:c.-154_-139delCACACACACACACACA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004994.3(MMP9):​c.-154_-139delCACACACACACACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 990,446 control chromosomes in the GnomAD database, including 744 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (59 hom., cov: 0)
  • Exomes 𝑓: 0.020 (685 hom.)
• Consequence: MMP9 NM_004994.3 upstream_gene
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 20-46008772-CCACACACACACACACA-C is Benign according to our data. Variant chr20-46008772-CCACACACACACACACA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1326104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0233 (3300/141592) while in subpopulation AMR AF = 0.0383 (546/14262). AF 95% confidence interval is 0.0356. There are 59 homozygotes in GnomAd4. There are 1584 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3300 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.-154_-139delCACACACACACACACA		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_-139delCACACACACACACACA		upstream_gene	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.-154_-139delCACACACACACACACA		upstream_gene	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.-154_-139delCACACACACACACACA		upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3300 AN: 141492 Hom.: 59 Cov.: 0

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00446

Gnomad AMR AF: 0.0383

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.00228

Gnomad MID AF: 0.0194

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0230

GnomAD4 exome AF: 0.0203 AC: 17237 AN: 848854 Hom.: 685 AF XY: 0.0199 AC XY: 8591 AN XY: 432356

African (AFR) AF: 0.0319 AC: 603 AN: 18914

American (AMR) AF: 0.0203 AC: 641 AN: 31600

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 345 AN: 19446

East Asian (EAS) AF: 0.000745 AC: 21 AN: 28172

South Asian (SAS) AF: 0.0116 AC: 736 AN: 63394

European-Finnish (FIN) AF: 0.00496 AC: 155 AN: 31238

Middle Eastern (MID) AF: 0.0309 AC: 91 AN: 2948

European-Non Finnish (NFE) AF: 0.0225 AC: 13838 AN: 614842

Other (OTH) AF: 0.0211 AC: 807 AN: 38300

GnomAD4 genome AF: 0.0233 AC: 3300 AN: 141592 Hom.: 59 Cov.: 0 AF XY: 0.0232 AC XY: 1584 AN XY: 68274

African (AFR) AF: 0.0334 AC: 1241 AN: 37188

American (AMR) AF: 0.0383 AC: 546 AN: 14262

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 55 AN: 3394

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

South Asian (SAS) AF: 0.0134 AC: 56 AN: 4184

European-Finnish (FIN) AF: 0.00228 AC: 21 AN: 9226

Middle Eastern (MID) AF: 0.0210 AC: 6 AN: 286

European-Non Finnish (NFE) AF: 0.0201 AC: 1327 AN: 65884

Other (OTH) AF: 0.0228 AC: 44 AN: 1928

Alfa AF: 0.00 Hom.: 555

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;