chr20-46014472-G-A

Position:

chr20-46014472-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004994.3(MMP9):c.2003G>A(p.Arg668Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,549,446 control chromosomes in the GnomAD database, including 19,464 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1940 hom., cov: 32)

Exomes 𝑓: 0.15 ( 17524 hom. )

Consequence

MMP9
NM_004994.3 missense, splice_region

Scores

Splicing: ADA: 0.00001114

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.190

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:

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

SLC12A5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029470026).

BP6

Variant 20-46014472-G-A is Benign according to our data. Variant chr20-46014472-G-A is described in ClinVar as [Benign]. Clinvar id is 338559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP9	NM_004994.3 linkuse as main transcript	c.2003G>A	p.Arg668Gln	missense_variant, splice_region_variant	12/13	ENST00000372330.3	NP_004985.2
SLC12A5-AS1	NR_147699.1 linkuse as main transcript	n.985C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP9	ENST00000372330.3 linkuse as main transcript	c.2003G>A	p.Arg668Gln	missense_variant, splice_region_variant	12/13	1	NM_004994.3	ENSP00000361405	P1
SLC12A5-AS1	ENST00000535913.2 linkuse as main transcript	n.985C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23790

AN:

152078

Hom.:

1942

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.0940

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.170

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.152

GnomAD3 exomes

AF:

0.159

AC:

24487

AN:

154326

Hom.:

2275

AF XY:

0.169

AC XY:

13811

AN XY:

81540

show subpopulations

Gnomad AFR exome

AF:

0.177

Gnomad AMR exome

AF:

0.0695

Gnomad ASJ exome

AF:

0.161

Gnomad EAS exome

AF:

0.127

Gnomad SAS exome

AF:

0.296

Gnomad FIN exome

AF:

0.169

Gnomad NFE exome

AF:

0.144

Gnomad OTH exome

AF:

0.161

GnomAD4 exome

AF:

0.153

AC:

213619

AN:

1397250

Hom.:

17524

Cov.:

AF XY:

0.157

AC XY:

108526

AN XY:

689314

show subpopulations

Gnomad4 AFR exome

AF:

0.181

Gnomad4 AMR exome

AF:

0.0745

Gnomad4 ASJ exome

AF:

0.159

Gnomad4 EAS exome

AF:

0.164

Gnomad4 SAS exome

AF:

0.290

Gnomad4 FIN exome

AF:

0.164

Gnomad4 NFE exome

AF:

0.143

Gnomad4 OTH exome

AF:

0.162

GnomAD4 genome

AF:

0.156

AC:

23806

AN:

152196

Hom.:

1940

Cov.:

AF XY:

0.158

AC XY:

11759

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.177

Gnomad4 AMR

AF:

0.0938

Gnomad4 ASJ

AF:

0.157

Gnomad4 EAS

AF:

0.148

Gnomad4 SAS

AF:

0.298

Gnomad4 FIN

AF:

0.170

Gnomad4 NFE

AF:

0.148

Gnomad4 OTH

AF:

0.156

Alfa

AF:

0.142

Hom.:

2768

Bravo

AF:

0.149

TwinsUK

AF:

0.138

AC:

511

ALSPAC

AF:

0.147

AC:

565

ESP6500AA

AF:

0.159

AC:

614

ESP6500EA

AF:

0.117

AC:

860

ExAC

AF:

0.115

AC:

5306

Asia WGS

AF:

0.210

AC:

728

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 25639450, 16631427, 19064570, 22142952, 23128247) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Metaphyseal anadysplasia 2

Benign:2

Benign, 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). 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.048

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.33

MutationTaster

Benign

1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

0.30

REVEL

Benign

0.075

Sift

Benign

1.0

Sift4G

Benign

0.65

Polyphen

0.010

Vest4

0.049

ClinPred

0.0080

GERP RS

-9.3

Varity_R

0.071

gMVP

0.066

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.0

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