20-46008971-C-T

Variant names:

• chr20-46008971-C-T
• rs28763885
• NM_004994.3:c.45C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004994.3(MMP9):​c.45C>T​(p.Gly15Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,613,970 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G15G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: MMP9 NM_004994.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00200
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 20-46008971-C-T is Benign according to our data. Variant chr20-46008971-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 338544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.002 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1694/152228) while in subpopulation AFR AF = 0.039 (1618/41534). AF 95% confidence interval is 0.0374. There are 34 homozygotes in GnomAd4. There are 778 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1694 Unknown,AD gene.

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.45C>T	p.Gly15Gly	synonymous	Exon 1 of 13	NP_004985.2	P14780

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	ENST00000372330.3	TSL:1 MANE Select	c.45C>T	p.Gly15Gly	synonymous	Exon 1 of 13	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.45C>T	p.Gly15Gly	synonymous	Exon 1 of 13	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.45C>T	p.Gly15Gly	synonymous	Exon 1 of 12	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1693 AN: 152110 Hom.: 34 Cov.: 31

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00276 AC: 692 AN: 250852 AF XY: 0.00192

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00110 AC: 1615 AN: 1461742 Hom.: 27 Cov.: 33 AF XY: 0.000917 AC XY: 667 AN XY: 727170

African (AFR) AF: 0.0389 AC: 1301 AN: 33476

American (AMR) AF: 0.00246 AC: 110 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111952

Other (OTH) AF: 0.00272 AC: 164 AN: 60382

GnomAD4 genome AF: 0.0111 AC: 1694 AN: 152228 Hom.: 34 Cov.: 31 AF XY: 0.0105 AC XY: 778 AN XY: 74432

African (AFR) AF: 0.0390 AC: 1618 AN: 41534

American (AMR) AF: 0.00373 AC: 57 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00756 Hom.: 8

Bravo AF: 0.0126

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.6
DANN	Benign	0.66
PhyloP100		-0.0020
PromoterAI		-0.011	Neutral
Mutation Taster		=100/0	polymorphism

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: rs28763885; hg19: chr20-44637610;