rs3918256

chr20-46012320-G-A

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: -0.572

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 338554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46012320-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MMP9	NM_004994.3	c.1174+7G>A		splice_region_variant, intron_variant		ENST00000372330.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3	c.1174+7G>A		splice_region_variant, intron_variant		1	NM_004994.3	P1

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

GnomAD3 exomes AF: 0.428 AC: 106041 AN: 247912 Hom.: 26860 AF XY: 0.438 AC XY: 58944 AN XY: 134698

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 SAS exome AF: 0.329

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

Gnomad4 AFR exome AF: 0.237

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.508

Gnomad4 EAS exome AF: 0.00141

Gnomad4 SAS exome AF: 0.334

Gnomad4 FIN exome AF: 0.492

Gnomad4 NFE exome AF: 0.580

Gnomad4 OTH exome AF: 0.497

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

Gnomad4 AFR AF: 0.253

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.480

Gnomad4 NFE AF: 0.576

Gnomad4 OTH AF: 0.466

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal anadysplasia 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.3
Dann	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs3918256; hg19: chr20-44640959; COSMIC: COSV63434001; COSMIC: COSV63434001;