20-46008996-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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. R24H) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 707836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP9	NM_004994.3	c.70C>T	p.Arg24Cys	missense_variant	1/13	ENST00000372330.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3	c.70C>T	p.Arg24Cys	missense_variant	1/13	1	NM_004994.3	P1

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

GnomAD3 exomes AF: 0.00351 AC: 879 AN: 250714 Hom.: 4 AF XY: 0.00357 AC XY: 484 AN XY: 135546

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 SAS exome AF: 0.00108

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

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.00455

Gnomad4 OTH exome AF: 0.00306

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

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0147

Gnomad4 NFE AF: 0.00547

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00444 Hom.: 7

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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal anadysplasia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

- -

MMP9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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
Varity_R		0.11
gMVP		0.49

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

Publications

LitVar

Other links and lift over

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