rs8125581

chr20-46010604-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_004994.3(MMP9):c.493G>A(p.Asp165Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: MMP9 NM_004994.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.91

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity MMP9_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP9	NM_004994.3	c.493G>A	p.Asp165Asn	missense_variant	3/13	ENST00000372330.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3	c.493G>A	p.Asp165Asn	missense_variant	3/13	1	NM_004994.3	P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000300 AC: 75 AN: 250346 Hom.: 0 AF XY: 0.000310 AC XY: 42 AN XY: 135502

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000442

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000535 AC: 782 AN: 1461650 Hom.: 0 Cov.: 33 AF XY: 0.000523 AC XY: 380 AN XY: 727110

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000646

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74374

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000558

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000407 Hom.: 0

Bravo AF: 0.000389

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 165 of the MMP9 protein (p.Asp165Asn). This variant is present in population databases (rs8125581, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MMP9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1414399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MMP9 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.95
MVP		0.90
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.78
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8125581; hg19: chr20-44639243;