rs144023823

Variant names:

• chr20-46008996-C-T
• rs144023823
• NM_004994.3:c.70C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004994.3(MMP9):​c.70C>T​(p.Arg24Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,613,976 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0041 (25 hom.)
• Consequence: MMP9 NM_004994.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.595
• Publications: 16 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006632149).
• BP6: Variant 20-46008996-C-T is Benign according to our data. Variant chr20-46008996-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 707836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 576 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.70C>T	p.Arg24Cys	missense	Exon 1 of 13	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.70C>T	p.Arg24Cys	missense	Exon 1 of 13	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.70C>T	p.Arg24Cys	missense	Exon 1 of 13	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.70C>T	p.Arg24Cys	missense	Exon 1 of 12	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 576 AN: 152138 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0147

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00547

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00351 AC: 879 AN: 250714 AF XY: 0.00357

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.00520

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00411 AC: 6010 AN: 1461720 Hom.: 25 Cov.: 33 AF XY: 0.00405 AC XY: 2942 AN XY: 727134

African (AFR) AF: 0.000508 AC: 17 AN: 33476

American (AMR) AF: 0.000313 AC: 14 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00122 AC: 105 AN: 86212

European-Finnish (FIN) AF: 0.0114 AC: 609 AN: 53402

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00455 AC: 5063 AN: 1111934

Other (OTH) AF: 0.00306 AC: 185 AN: 60390

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152256 Hom.: 1 Cov.: 31 AF XY: 0.00403 AC XY: 300 AN XY: 74444

African (AFR) AF: 0.000530 AC: 22 AN: 41544

American (AMR) AF: 0.00137 AC: 21 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0147 AC: 156 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00547 AC: 372 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00438 Hom.: 11

Bravo AF: 0.00238

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00383 AC: 465

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00398

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Metaphyseal anadysplasia 2 (1)
-	-	1	MMP9-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.59
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.19
Sift	Benign	0.038	D
Sift4G	Uncertain	0.054	T
Polyphen		0.99	D
Vest4		0.34
MVP		0.68
ClinPred		0.020	T
GERP RS		3.3
PromoterAI		-0.0057	Neutral
Varity_R		0.11
gMVP		0.49
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144023823; hg19: chr20-44637635; COSMIC: COSV100959182; COSMIC: COSV100959182;