20-46008985-C-T

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.59C>T(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,613,788 control chromosomes in the GnomAD database, including 1,152 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A20T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (172 hom., cov: 31)
  • Exomes 𝑓: 0.026 (980 hom.)
• Consequence: MMP9 NM_004994.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.15

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017846525).
• BP6: Variant 20-46008985-C-T is Benign according to our data. Variant chr20-46008985-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 338546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46008985-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP9	NM_004994.3	c.59C>T	p.Ala20Val	missense_variant	1/13	ENST00000372330.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3	c.59C>T	p.Ala20Val	missense_variant	1/13	1	NM_004994.3	P1

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4357 AN: 152050 Hom.: 169 Cov.: 31

Gnomad AFR AF: 0.00763

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0408 AC: 10234 AN: 250604 Hom.: 525 AF XY: 0.0365 AC XY: 4943 AN XY: 135516

Gnomad AFR exome AF: 0.00581

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.0513

Gnomad EAS exome AF: 0.0308

Gnomad SAS exome AF: 0.0280

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0394

GnomAD4 exome AF: 0.0262 AC: 38315 AN: 1461620 Hom.: 980 Cov.: 34 AF XY: 0.0259 AC XY: 18822 AN XY: 727094

Gnomad4 AFR exome AF: 0.00493

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.0534

Gnomad4 EAS exome AF: 0.0398

Gnomad4 SAS exome AF: 0.0279

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.0208

Gnomad4 OTH exome AF: 0.0294

GnomAD4 genome AF: 0.0287 AC: 4363 AN: 152168 Hom.: 172 Cov.: 31 AF XY: 0.0307 AC XY: 2286 AN XY: 74404

Gnomad4 AFR AF: 0.00761

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.0541

Gnomad4 EAS AF: 0.0303

Gnomad4 SAS AF: 0.0249

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0210

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0191 Hom.: 30

Bravo AF: 0.0352

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0223 AC: 192

ExAC AF: 0.0344 AC: 4174

Asia WGS AF: 0.0290 AC: 100 AN: 3478

EpiCase AF: 0.0216

EpiControl AF: 0.0227

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Metaphyseal anadysplasia 2 Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.70	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.053
Sift	Benign	0.22	T
Sift4G	Benign	0.53	T
Polyphen		0.35	B
Vest4		0.087
ClinPred		0.0085	T
GERP RS		2.6
Varity_R		0.038
gMVP		0.51

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: rs1805088; hg19: chr20-44637624;