rs2274755

Variant names:

• chr20-46011053-G-T
• rs2274755
• NM_004994.3:c.649+3G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004994.3(MMP9):​c.649+3G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,514 control chromosomes in the GnomAD database, including 20,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1883 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18137 hom.)
• Consequence: MMP9 NM_004994.3 splice_region, intron
• Scores: Splicing: ADA: 0.9652
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.22
• Publications: 63 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 -16 ACMG points.

• BP6: Variant 20-46011053-G-T is Benign according to our data. Variant chr20-46011053-G-T is described in ClinVar as Benign. ClinVar VariationId is 338548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP9	NM_004994.3	c.649+3G>T		splice_region_variant, intron_variant	Intron 4 of 12	ENST00000372330.3	NP_004985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP9	ENST00000372330.3	c.649+3G>T		splice_region_variant, intron_variant	Intron 4 of 12	1	NM_004994.3	ENSP00000361405.3

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23398 AN: 152084 Hom.: 1885 Cov.: 33

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0934

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.154 AC: 38552 AN: 250870 AF XY: 0.163

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0644

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.130

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.152 AC: 222093 AN: 1461312 Hom.: 18137 Cov.: 44 AF XY: 0.157 AC XY: 113780 AN XY: 726998

African (AFR) AF: 0.172 AC: 5752 AN: 33480

American (AMR) AF: 0.0693 AC: 3101 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4151 AN: 26134

East Asian (EAS) AF: 0.151 AC: 5978 AN: 39700

South Asian (SAS) AF: 0.283 AC: 24414 AN: 86256

European-Finnish (FIN) AF: 0.165 AC: 8738 AN: 52864

Middle Eastern (MID) AF: 0.155 AC: 892 AN: 5768

European-Non Finnish (NFE) AF: 0.143 AC: 159379 AN: 1112000

Other (OTH) AF: 0.160 AC: 9688 AN: 60386

GnomAD4 genome AF: 0.154 AC: 23415 AN: 152202 Hom.: 1883 Cov.: 33 AF XY: 0.155 AC XY: 11565 AN XY: 74410

African (AFR) AF: 0.168 AC: 6989 AN: 41536

American (AMR) AF: 0.0932 AC: 1426 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3470

East Asian (EAS) AF: 0.143 AC: 737 AN: 5170

South Asian (SAS) AF: 0.292 AC: 1412 AN: 4828

European-Finnish (FIN) AF: 0.172 AC: 1818 AN: 10596

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

European-Non Finnish (NFE) AF: 0.148 AC: 10046 AN: 67990

Other (OTH) AF: 0.154 AC: 326 AN: 2112

Alfa AF: 0.143 Hom.: 2888

Bravo AF: 0.146

Asia WGS AF: 0.205 AC: 712 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.142

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal anadysplasia 2 Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16631427, 25525159) -

not specified Benign:1

Aug 10, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		3.2
Mutation Taster		=3/97	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.34		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2274755; hg19: chr20-44639692; COSMIC: COSV63434098; COSMIC: COSV63434098;