chr20-46008939-C-A

Position:

• chr20-46008939-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004994.3(MMP9):​c.13C>A​(p.Gln5Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MMP9 NM_004994.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.779

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14896137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP9	NM_004994.3	c.13C>A	p.Gln5Lys	missense_variant	1/13	ENST00000372330.3	NP_004985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP9	ENST00000372330.3	c.13C>A	p.Gln5Lys	missense_variant	1/13	1	NM_004994.3	ENSP00000361405.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461482 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2024

The c.13C>A (p.Q5K) alteration is located in exon 1 (coding exon 1) of the MMP9 gene. This alteration results from a C to A substitution at nucleotide position 13, causing the glutamine (Q) at amino acid position 5 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.15
Sift	Benign	0.23	T
Sift4G	Benign	0.96	T
Polyphen		0.43	B
Vest4		0.37
MutPred		0.51		Gain of methylation at Q5 (P = 0.0176);
MVP		0.36
ClinPred		0.36	T
GERP RS		4.5
Varity_R		0.25
gMVP		0.53

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: rs1416299149; hg19: chr20-44637578;