20-46013767-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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:6
• 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 Benign. Variant got -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 id is 282093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46013767-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP9	NM_004994.3	c.1721G>C	p.Arg574Pro	missense_variant	10/13	ENST00000372330.3
SLC12A5-AS1	NR_147699.1	n.1690C>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3	c.1721G>C	p.Arg574Pro	missense_variant	10/13	1	NM_004994.3	P1
SLC12A5-AS1	ENST00000535913.2	n.1690C>G		non_coding_transcript_exon_variant	3/3	2

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

GnomAD3 exomes AF: 0.876 AC: 219719 AN: 250788 Hom.: 98051 AF XY: 0.887 AC XY: 120276 AN XY: 135636

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 SAS exome AF: 0.860

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

Gnomad4 AFR exome AF: 0.842

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.955

Gnomad4 EAS exome AF: 0.737

Gnomad4 SAS exome AF: 0.860

Gnomad4 FIN exome AF: 0.919

Gnomad4 NFE exome AF: 0.956

Gnomad4 OTH exome AF: 0.926

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

Gnomad4 AFR AF: 0.845

Gnomad4 AMR AF: 0.808

Gnomad4 ASJ AF: 0.952

Gnomad4 EAS AF: 0.759

Gnomad4 SAS AF: 0.860

Gnomad4 FIN AF: 0.916

Gnomad4 NFE AF: 0.955

Gnomad4 OTH AF: 0.898

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal anadysplasia 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	This variant is associated with the following publications: (PMID: 18512818, 22729913, 19633731, 16574953, 25639450) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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; COSMIC: COSV63434590;