rs2250889

Positions:

• chr20-46013767-G-A
• chr20-46013767-G-C
• chr20-46013767-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004994.3(MMP9):​c.1721G>A​(p.Arg574Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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. R574P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MMP9 NM_004994.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.934

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]

SLC12A5-AS1 (HGNC:53143): (SLC12A5 and MMP9 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047951788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP9	NM_004994.3	c.1721G>A	p.Arg574Gln	missense_variant	10/13	ENST00000372330.3	NP_004985.2
SLC12A5-AS1	NR_147699.1	n.1690C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP9	ENST00000372330.3	c.1721G>A	p.Arg574Gln	missense_variant	10/13	1	NM_004994.3	ENSP00000361405	P1
SLC12A5-AS1	ENST00000535913.2	n.1690C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 76

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.58	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.088
Sift	Benign	0.037	D
Sift4G	Benign	0.25	T
Polyphen		0.0060	B
Vest4		0.11
MutPred		0.41		Loss of MoRF binding (P = 0.0447);
MVP		0.38
ClinPred		0.38	T
GERP RS		3.9
Varity_R		0.079
gMVP		0.50

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: rs2250889; hg19: chr20-44642406;