chr20-46008772-CCACACACACA-C

Variant names:

• chr20-46008772-CCACACACACA-C
• rs2234681
• NM_004994.3:c.-154_-145delCACACACACA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_004994.3(MMP9):​c.-154_-145delCACACACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 995,694 control chromosomes in the GnomAD database, including 37 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0095 (28 hom., cov: 0)
  • Exomes 𝑓: 0.0032 (9 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00953 (1349/141622) while in subpopulation AFR AF = 0.033 (1227/37184). AF 95% confidence interval is 0.0315. There are 28 homozygotes in GnomAd4. There are 640 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1349 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_-145delCACACACACA		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_-145delCACACACACA		upstream_gene	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.-154_-145delCACACACACA		upstream_gene	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.-154_-145delCACACACACA		upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.00949 AC: 1343 AN: 141520 Hom.: 28 Cov.: 0

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000589

Gnomad EAS AF: 0.000459

Gnomad SAS AF: 0.00453

Gnomad FIN AF: 0.000108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000622

Gnomad OTH AF: 0.00838

GnomAD4 exome AF: 0.00321 AC: 2738 AN: 854072 Hom.: 9 AF XY: 0.00336 AC XY: 1461 AN XY: 434966

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

African (AFR) AF: 0.0329 AC: 622 AN: 18894

American (AMR) AF: 0.00354 AC: 112 AN: 31630

Ashkenazi Jewish (ASJ) AF: 0.00323 AC: 63 AN: 19532

East Asian (EAS) AF: 0.00467 AC: 131 AN: 28052

South Asian (SAS) AF: 0.0101 AC: 640 AN: 63326

European-Finnish (FIN) AF: 0.00264 AC: 83 AN: 31386

Middle Eastern (MID) AF: 0.00405 AC: 12 AN: 2960

European-Non Finnish (NFE) AF: 0.00142 AC: 883 AN: 619756

Other (OTH) AF: 0.00498 AC: 192 AN: 38536

⚠️ 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: 0.00953 AC: 1349 AN: 141622 Hom.: 28 Cov.: 0 AF XY: 0.00937 AC XY: 640 AN XY: 68284

African (AFR) AF: 0.0330 AC: 1227 AN: 37184

American (AMR) AF: 0.00287 AC: 41 AN: 14270

Ashkenazi Jewish (ASJ) AF: 0.000589 AC: 2 AN: 3394

East Asian (EAS) AF: 0.000460 AC: 2 AN: 4344

South Asian (SAS) AF: 0.00454 AC: 19 AN: 4186

European-Finnish (FIN) AF: 0.000108 AC: 1 AN: 9234

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

European-Non Finnish (NFE) AF: 0.000622 AC: 41 AN: 65900

Other (OTH) AF: 0.00830 AC: 16 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		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;