chr20-46008985-C-T

Variant names:

• chr20-46008985-C-T
• rs1805088
• NM_004994.3:c.59C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:4
• Conservation: PhyloP100: 2.15
• Publications: 34 publications found

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 Gene-Disease associations (from GenCC):

• metaphyseal anadysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• metaphyseal anadysplasia 2

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 338546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004994.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	NM_004994.3	MANE Select	c.59C>T	p.Ala20Val	missense	Exon 1 of 13	NP_004985.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	ENST00000372330.3	TSL:1 MANE Select	c.59C>T	p.Ala20Val	missense	Exon 1 of 13	ENSP00000361405.3
	MMP9	ENST00000898203.1		c.59C>T	p.Ala20Val	missense	Exon 1 of 13	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.59C>T	p.Ala20Val	missense	Exon 1 of 12	ENSP00000568263.1

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

GnomAD2 exomes AF: 0.0408 AC: 10234 AN: 250604 AF XY: 0.0365

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 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

African (AFR) AF: 0.00493 AC: 165 AN: 33476

American (AMR) AF: 0.151 AC: 6731 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0534 AC: 1396 AN: 26134

East Asian (EAS) AF: 0.0398 AC: 1580 AN: 39690

South Asian (SAS) AF: 0.0279 AC: 2402 AN: 86220

European-Finnish (FIN) AF: 0.0193 AC: 1031 AN: 53376

Middle Eastern (MID) AF: 0.0160 AC: 92 AN: 5766

European-Non Finnish (NFE) AF: 0.0208 AC: 23143 AN: 1111906

Other (OTH) AF: 0.0294 AC: 1775 AN: 60384

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

African (AFR) AF: 0.00761 AC: 316 AN: 41524

American (AMR) AF: 0.119 AC: 1815 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

East Asian (EAS) AF: 0.0303 AC: 156 AN: 5156

South Asian (SAS) AF: 0.0249 AC: 120 AN: 4824

European-Finnish (FIN) AF: 0.0184 AC: 195 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0210 AC: 1426 AN: 67994

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

Alfa AF: 0.0186 Hom.: 77

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Metaphyseal anadysplasia 2 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.1
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
PromoterAI		-0.0038	Neutral
Varity_R		0.038
gMVP		0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1805088; hg19: chr20-44637624; COSMIC: COSV107466732; COSMIC: COSV107466732;