20-46013767-G-C

Variant names:

• chr20-46013767-G-C
• rs2250889
• NM_004994.3:c.1721G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004994.3(MMP9):​c.1721G>C​(p.Arg574Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,613,230 control chromosomes in the GnomAD database, including 697,146 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R574L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.90 (61725 hom., cov: 34)
  • Exomes 𝑓: 0.93 (635421 hom.)
• Consequence: MMP9 NM_004994.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.934
• Publications: 172 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.9859115E-7).
• BP6: Variant 20-46013767-G-C is Benign according to our data. Variant chr20-46013767-G-C is described in ClinVar as Benign. ClinVar VariationId is 282093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004994.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	NM_004994.3	MANE Select	c.1721G>C	p.Arg574Pro	missense	Exon 10 of 13	NP_004985.2
	SLC12A5-AS1	NR_147699.1		n.1690C>G		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	ENST00000372330.3	TSL:1 MANE Select	c.1721G>C	p.Arg574Pro	missense	Exon 10 of 13	ENSP00000361405.3
	SLC12A5-AS1	ENST00000535913.2	TSL:2	n.1690C>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.897 AC: 136526 AN: 152144 Hom.: 61705 Cov.: 34

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.991

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.952

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.859

Gnomad FIN AF: 0.916

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.955

Gnomad OTH AF: 0.903

GnomAD2 exomes AF: 0.876 AC: 219719 AN: 250788 AF XY: 0.887

Gnomad AFR exome AF: 0.847

Gnomad AMR exome AF: 0.643

Gnomad ASJ exome AF: 0.959

Gnomad EAS exome AF: 0.778

Gnomad FIN exome AF: 0.918

Gnomad NFE exome AF: 0.954

Gnomad OTH exome AF: 0.907

GnomAD4 exome AF: 0.930 AC: 1358563 AN: 1460968 Hom.: 635421 Cov.: 76 AF XY: 0.929 AC XY: 675346 AN XY: 726778

African (AFR) AF: 0.842 AC: 28173 AN: 33456

American (AMR) AF: 0.663 AC: 29603 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.955 AC: 24952 AN: 26130

East Asian (EAS) AF: 0.737 AC: 29250 AN: 39694

South Asian (SAS) AF: 0.860 AC: 74107 AN: 86214

European-Finnish (FIN) AF: 0.919 AC: 49086 AN: 53402

Middle Eastern (MID) AF: 0.920 AC: 4722 AN: 5130

European-Non Finnish (NFE) AF: 0.956 AC: 1062821 AN: 1111956

Other (OTH) AF: 0.926 AC: 55849 AN: 60320

GnomAD4 genome AF: 0.897 AC: 136587 AN: 152262 Hom.: 61725 Cov.: 34 AF XY: 0.893 AC XY: 66455 AN XY: 74450

African (AFR) AF: 0.845 AC: 35108 AN: 41548

American (AMR) AF: 0.808 AC: 12360 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.952 AC: 3305 AN: 3472

East Asian (EAS) AF: 0.759 AC: 3896 AN: 5136

South Asian (SAS) AF: 0.860 AC: 4153 AN: 4830

European-Finnish (FIN) AF: 0.916 AC: 9731 AN: 10624

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.955 AC: 64952 AN: 68028

Other (OTH) AF: 0.898 AC: 1899 AN: 2114

Alfa AF: 0.938 Hom.: 45699

Bravo AF: 0.884

TwinsUK AF: 0.959 AC: 3555

ALSPAC AF: 0.955 AC: 3680

ESP6500AA AF: 0.855 AC: 3767

ESP6500EA AF: 0.953 AC: 8198

ExAC AF: 0.883 AC: 107267

Asia WGS AF: 0.755 AC: 2626 AN: 3478

EpiCase AF: 0.955

EpiControl AF: 0.954

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal anadysplasia 2 Benign:3

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18512818, 22729913, 19633731, 16574953, 25639450)

not specified Benign:1

Nov 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Benign	0.75
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.093	T
MetaRNN	Benign	8.0e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.5	N
PhyloP100		0.93
PrimateAI	Benign	0.35	T
PROVEAN	Benign	3.9	N
REVEL	Benign	0.053
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.041
ClinPred		0.012	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.74
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2250889; hg19: chr20-44642406; COSMIC: COSV63434590;