20-46008772-CCACACACACACACACACACACACACACACACACA-CCACACACACACACACACACACACACACA

Variant names:

• chr20-46008772-CCACACA-C
• rs2234681
• NM_004994.3:c.-154_-149delCACACA

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_-149delCACACA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 988,898 control chromosomes in the GnomAD database, including 350 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (266 hom., cov: 0)
  • Exomes 𝑓: 0.037 (84 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-CCACACA-C is Benign according to our data. Variant chr20-46008772-CCACACA-C is described in ClinVar as Benign. ClinVar VariationId is 1261573.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 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_-149delCACACA		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_-149delCACACA		upstream_gene	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.-154_-149delCACACA		upstream_gene	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.-154_-149delCACACA		upstream_gene	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6046 AN: 141400 Hom.: 265 Cov.: 0

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0167

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.00914

Gnomad EAS AF: 0.0315

Gnomad SAS AF: 0.0401

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.0290

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0320

GnomAD4 exome AF: 0.0372 AC: 31538 AN: 847396 Hom.: 84 AF XY: 0.0380 AC XY: 16398 AN XY: 431520

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

African (AFR) AF: 0.113 AC: 2109 AN: 18684

American (AMR) AF: 0.0618 AC: 1932 AN: 31258

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 740 AN: 19310

East Asian (EAS) AF: 0.161 AC: 4407 AN: 27362

South Asian (SAS) AF: 0.0529 AC: 3316 AN: 62718

European-Finnish (FIN) AF: 0.0496 AC: 1538 AN: 30982

Middle Eastern (MID) AF: 0.0370 AC: 109 AN: 2942

European-Non Finnish (NFE) AF: 0.0255 AC: 15720 AN: 615962

Other (OTH) AF: 0.0437 AC: 1667 AN: 38178

⚠️ 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: 0.0428 AC: 6054 AN: 141502 Hom.: 266 Cov.: 0 AF XY: 0.0431 AC XY: 2937 AN XY: 68222

African (AFR) AF: 0.108 AC: 4027 AN: 37138

American (AMR) AF: 0.0217 AC: 309 AN: 14256

Ashkenazi Jewish (ASJ) AF: 0.00914 AC: 31 AN: 3392

East Asian (EAS) AF: 0.0313 AC: 136 AN: 4342

South Asian (SAS) AF: 0.0399 AC: 167 AN: 4184

European-Finnish (FIN) AF: 0.0244 AC: 225 AN: 9206

Middle Eastern (MID) AF: 0.0280 AC: 8 AN: 286

European-Non Finnish (NFE) AF: 0.0163 AC: 1074 AN: 65876

Other (OTH) AF: 0.0322 AC: 62 AN: 1926

Alfa AF: 0.0197 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;