rs1805088

Positions:

• chr20-46008985-C-G
• chr20-46008985-C-T

Variant summary

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

The NM_004994.3(MMP9):​c.59C>G​(p.Ala20Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A20V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MMP9 NM_004994.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP9	NM_004994.3	c.59C>G	p.Ala20Gly	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.59C>G	p.Ala20Gly	missense_variant	1/13	1	NM_004994.3	ENSP00000361405.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250604 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461636 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Benign	0.058	T
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.44		Loss of helix (P = 0.0237);
MVP		0.61
ClinPred		0.37	T
GERP RS		2.6
Varity_R		0.082
gMVP		0.54

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: rs1805088; hg19: chr20-44637624;