rs41529445

Positions:

chr20-46011266-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004994.3(MMP9):c.773C>T(p.Thr258Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00154 in 1,611,326 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

MMP9
NM_004994.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 6.10

Variant links:

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]

MMP9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.091989696).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP9	NM_004994.3 linkuse as main transcript	c.773C>T	p.Thr258Ile	missense_variant	5/13	ENST00000372330.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3 linkuse as main transcript	c.773C>T	p.Thr258Ile	missense_variant	5/13	1	NM_004994.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

226

AN:

151860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00289

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.000971

AC:

242

AN:

249342

Hom.:

AF XY:

0.000888

AC XY:

120

AN XY:

135104

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00155

AC:

2255

AN:

1459346

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1061

AN XY:

725952

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00384

Gnomad4 NFE exome

AF:

0.00170

Gnomad4 OTH exome

AF:

0.00196

GnomAD4 genome

AF:

0.00149

AC:

226

AN:

151980

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00340

Gnomad4 NFE

AF:

0.00182

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000923

AC:

112

EpiCase

AF:

0.00180

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2018	The T258I variant in the MMP9 gene has not been reported previously as a pathogenic variant to our knowledge. This variant has been published in a study of the association between MMP9 genotype and abdominal aortic aneurysm, however, T258I did not show significantly different protein amount or enzymatic activity compared to wild-type (Duellman et al., 2012). The T258I variant is observed in 84/24,268 (0.35%) alleles from individuals of Finnish European background in large population cohorts (Lek et al., 2016). The T258I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although in silico analyses, which includes protein predictors and evolutionary conservation, support a deleterious effect, in vitro functional studies demonstrate no damaging effect (Duellmen et al., 2012). We interpret T258I as a variant of uncertain significance. -

Metaphyseal anadysplasia 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.066

MetaRNN

Benign

0.092

MetaSVM

Uncertain

0.13

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.86

MVP

0.97

ClinPred

0.12

GERP RS

4.6

Varity_R

0.64

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over