rs2236416

Variant names:

• chr20-46011936-A-G
• rs2236416
• NM_004994.3:c.997+189A>G

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.997+189A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,070 control chromosomes in the GnomAD database, including 1,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.14 (1578 hom., cov: 33)
• Consequence: MMP9 NM_004994.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.58
• Publications: 39 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 (BayesDel_noAF=-0.83).
• BP6: Variant 20-46011936-A-G is Benign according to our data. Variant chr20-46011936-A-G is described in ClinVar as Benign. ClinVar VariationId is 1260043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP9	NM_004994.3	c.997+189A>G		intron_variant	Intron 6 of 12	ENST00000372330.3	NP_004985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP9	ENST00000372330.3	c.997+189A>G		intron_variant	Intron 6 of 12	1	NM_004994.3	ENSP00000361405.3

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21627 AN: 151952 Hom.: 1578 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0804

Gnomad AMR AF: 0.0903

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.142

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.142 AC: 21640 AN: 152070 Hom.: 1578 Cov.: 33 AF XY: 0.143 AC XY: 10620 AN XY: 74332

African (AFR) AF: 0.134 AC: 5555 AN: 41502

American (AMR) AF: 0.0901 AC: 1377 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 545 AN: 3470

East Asian (EAS) AF: 0.144 AC: 742 AN: 5162

South Asian (SAS) AF: 0.237 AC: 1142 AN: 4826

European-Finnish (FIN) AF: 0.172 AC: 1818 AN: 10558

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10039 AN: 67952

Other (OTH) AF: 0.146 AC: 308 AN: 2114

Alfa AF: 0.140 Hom.: 1856

Bravo AF: 0.134

Asia WGS AF: 0.182 AC: 633 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.11
DANN	Benign	0.29
PhyloP100		-1.6
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: rs2236416; hg19: chr20-44640575; COSMIC: COSV63433946; COSMIC: COSV63433946;