20-46008772-CCACACACACACACACACACACACACACACACACA-CCACACACACACACACACACACACACACACA

Variant names:

• chr20-46008772-CCACA-C
• rs2234681
• NM_004994.3:c.-154_-151delCACA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004994.3(MMP9):​c.-154_-151delCACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 975,740 control chromosomes in the GnomAD database, including 3,900 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3184 hom., cov: 0)
  • Exomes 𝑓: 0.11 (716 hom.)
• Consequence: MMP9 NM_004994.3 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.281
• 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-CCACA-C is Benign according to our data. Variant chr20-46008772-CCACA-C is described in ClinVar as Benign. ClinVar VariationId is 1231665.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

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_-151delCACA		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_-151delCACA		upstream_gene	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.-154_-151delCACA		upstream_gene	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.-154_-151delCACA		upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 28530 AN: 140886 Hom.: 3177 Cov.: 0

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.182

GnomAD4 exome AF: 0.113 AC: 94064 AN: 834764 Hom.: 716 AF XY: 0.115 AC XY: 48900 AN XY: 424894

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

African (AFR) AF: 0.155 AC: 2863 AN: 18496

American (AMR) AF: 0.195 AC: 6004 AN: 30724

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 2646 AN: 18930

East Asian (EAS) AF: 0.362 AC: 10031 AN: 27722

South Asian (SAS) AF: 0.144 AC: 8812 AN: 61346

European-Finnish (FIN) AF: 0.161 AC: 4849 AN: 30192

Middle Eastern (MID) AF: 0.120 AC: 348 AN: 2892

European-Non Finnish (NFE) AF: 0.0886 AC: 53803 AN: 606930

Other (OTH) AF: 0.125 AC: 4708 AN: 37532

⚠️ 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: 0.202 AC: 28544 AN: 140976 Hom.: 3184 Cov.: 0 AF XY: 0.205 AC XY: 13938 AN XY: 67942

African (AFR) AF: 0.227 AC: 8420 AN: 37022

American (AMR) AF: 0.245 AC: 3471 AN: 14186

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 706 AN: 3380

East Asian (EAS) AF: 0.504 AC: 2188 AN: 4338

South Asian (SAS) AF: 0.173 AC: 720 AN: 4166

European-Finnish (FIN) AF: 0.195 AC: 1784 AN: 9142

Middle Eastern (MID) AF: 0.189 AC: 53 AN: 280

European-Non Finnish (NFE) AF: 0.163 AC: 10708 AN: 65664

Other (OTH) AF: 0.181 AC: 345 AN: 1910

Alfa AF: 0.167 Hom.: 555

ClinVar

ClinVar submissions

Significance: 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		0.28

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;