rs41427445

chr20-46009039-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004994.3(MMP9):c.113A>G(p.Asn38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,613,776 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 31)
  • Exomes 𝑓: 0.011 (122 hom.)
• Consequence: MMP9 NM_004994.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00100

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003079921).
• BP6: Variant 20-46009039-A-G is Benign according to our data. Variant chr20-46009039-A-G is described in ClinVar as [Benign]. Clinvar id is 708035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46009039-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP9	NM_004994.3	c.113A>G	p.Asn38Ser	missense_variant	1/13	ENST00000372330.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3	c.113A>G	p.Asn38Ser	missense_variant	1/13	1	NM_004994.3	P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1621 AN: 152064 Hom.: 16 Cov.: 31

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00928 AC: 2324 AN: 250452 Hom.: 22 AF XY: 0.00923 AC XY: 1250 AN XY: 135402

Gnomad AFR exome AF: 0.00911

Gnomad AMR exome AF: 0.00611

Gnomad ASJ exome AF: 0.0473

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.00419

Gnomad FIN exome AF: 0.00312

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0114 AC: 16648 AN: 1461594 Hom.: 122 Cov.: 33 AF XY: 0.0112 AC XY: 8124 AN XY: 727052

Gnomad4 AFR exome AF: 0.00983

Gnomad4 AMR exome AF: 0.00647

Gnomad4 ASJ exome AF: 0.0501

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.00385

Gnomad4 FIN exome AF: 0.00324

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0107 AC: 1621 AN: 152182 Hom.: 16 Cov.: 31 AF XY: 0.0103 AC XY: 768 AN XY: 74410

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.0510

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0127 Hom.: 35

Bravo AF: 0.0117

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.00878 AC: 1066

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0128

EpiControl AF: 0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MMP9: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2021	This variant is associated with the following publications: (PMID: 22942228, 24627221) -

Metaphyseal anadysplasia 2 Benign:1

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	5.2
Dann	Benign	0.69
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.033
Sift	Benign	0.58	T
Sift4G	Benign	0.64	T
Polyphen		0.011	B
Vest4		0.17
MVP		0.34
ClinPred		0.0091	T
GERP RS		-3.1
Varity_R		0.11
gMVP		0.58

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: rs41427445; hg19: chr20-44637678; COSMIC: COSV99075747; COSMIC: COSV99075747;