rs3918256

Variant names:

• chr20-46012320-G-A
• rs3918256
• NM_004994.3:c.1174+7G>A

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.1174+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,612,638 control chromosomes in the GnomAD database, including 229,962 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (16140 hom., cov: 33)
  • Exomes 𝑓: 0.52 (213822 hom.)
• Consequence: MMP9 NM_004994.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001118
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.572
• Publications: 32 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 20-46012320-G-A is Benign according to our data. Variant chr20-46012320-G-A is described in ClinVar as Benign. ClinVar VariationId is 338554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP9	NM_004994.3	c.1174+7G>A		splice_region_variant, intron_variant	Intron 7 of 12	ENST00000372330.3	NP_004985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP9	ENST00000372330.3	c.1174+7G>A		splice_region_variant, intron_variant	Intron 7 of 12	1	NM_004994.3	ENSP00000361405.3

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65607 AN: 152040 Hom.: 16145 Cov.: 33

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.428 AC: 106041 AN: 247912 AF XY: 0.438

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.512

Gnomad EAS exome AF: 0.00231

Gnomad FIN exome AF: 0.482

Gnomad NFE exome AF: 0.579

Gnomad OTH exome AF: 0.488

GnomAD4 exome AF: 0.525 AC: 766383 AN: 1460480 Hom.: 213822 Cov.: 73 AF XY: 0.521 AC XY: 378728 AN XY: 726644

African (AFR) AF: 0.237 AC: 7938 AN: 33480

American (AMR) AF: 0.270 AC: 12090 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 13267 AN: 26136

East Asian (EAS) AF: 0.00141 AC: 56 AN: 39696

South Asian (SAS) AF: 0.334 AC: 28780 AN: 86252

European-Finnish (FIN) AF: 0.492 AC: 25645 AN: 52100

Middle Eastern (MID) AF: 0.549 AC: 3165 AN: 5768

European-Non Finnish (NFE) AF: 0.580 AC: 645420 AN: 1111946

Other (OTH) AF: 0.497 AC: 30022 AN: 60380

GnomAD4 genome AF: 0.431 AC: 65608 AN: 152158 Hom.: 16140 Cov.: 33 AF XY: 0.421 AC XY: 31277 AN XY: 74370

African (AFR) AF: 0.253 AC: 10498 AN: 41530

American (AMR) AF: 0.388 AC: 5923 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1771 AN: 3470

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5180

South Asian (SAS) AF: 0.315 AC: 1518 AN: 4814

European-Finnish (FIN) AF: 0.480 AC: 5078 AN: 10576

Middle Eastern (MID) AF: 0.582 AC: 170 AN: 292

European-Non Finnish (NFE) AF: 0.576 AC: 39127 AN: 67986

Other (OTH) AF: 0.466 AC: 985 AN: 2116

Alfa AF: 0.512 Hom.: 5525

Bravo AF: 0.413

Asia WGS AF: 0.156 AC: 547 AN: 3478

EpiCase AF: 0.580

EpiControl AF: 0.582

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Metaphyseal anadysplasia 2 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Sep 05, 2021

Genome-Nilou Lab

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	-0.83
CADD	Benign	2.3
DANN	Benign	0.80
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0020
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: rs3918256; hg19: chr20-44640959; COSMIC: COSV63434001; COSMIC: COSV63434001;