rs2274755

Positions:

• chr20-46011053-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004994.3(MMP9):​c.649+3G>T variant causes a splice donor 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_donor_region, intron
• Scores: Splicing: ADA: 0.9652
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.22

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 -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 id 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/exons	MANE	Protein	UniProt
MMP9	NM_004994.3	c.649+3G>T		splice_donor_region_variant, intron_variant		ENST00000372330.3	NP_004985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP9	ENST00000372330.3	c.649+3G>T		splice_donor_region_variant, intron_variant		1	NM_004994.3	ENSP00000361405	P1

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

GnomAD3 exomes AF: 0.154 AC: 38552 AN: 250870 Hom.: 3437 AF XY: 0.163 AC XY: 22093 AN XY: 135676

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 SAS exome AF: 0.291

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

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.0693

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.283

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.160

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

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0932

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.154

Alfa AF: 0.143 Hom.: 2139

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 16631427, 25525159) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.97

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

Publications

LitVar

Other links and lift over

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