rs3918254

Variant names:

• chr20-46011752-C-T
• rs3918254
• NM_004994.3:c.997+5C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-46011752-C-T
• chr20-46011752-C-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.997+5C>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 0.0129 in 1,609,020 control chromosomes in the GnomAD database, including 1,269 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 0.028 (218 hom., cov: 33)
  • Exomes 𝑓: 0.011 (1051 hom.)
• Consequence: MMP9 NM_004994.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004573
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.138
• 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=-0.67).
• BP6: Variant 20-46011752-C-T is Benign according to our data. Variant chr20-46011752-C-T is described in ClinVar as Benign. ClinVar VariationId is 338553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004994.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	NM_004994.3	MANE Select	c.997+5C>T		splice_region intron	N/A	NP_004985.2	P14780

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	ENST00000372330.3	TSL:1 MANE Select	c.997+5C>T		splice_region intron	N/A	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.934+5C>T		splice_region intron	N/A	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.868+5C>T		splice_region intron	N/A	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4273 AN: 152096 Hom.: 218 Cov.: 33

Gnomad AFR AF: 0.0601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.0416

Gnomad FIN AF: 0.00969

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0298 AC: 7250 AN: 243486 AF XY: 0.0278

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.0319

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.211

Gnomad FIN exome AF: 0.00943

Gnomad NFE exome AF: 0.000955

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0113 AC: 16425 AN: 1456806 Hom.: 1051 Cov.: 36 AF XY: 0.0115 AC XY: 8343 AN XY: 724836

African (AFR) AF: 0.0634 AC: 2119 AN: 33424

American (AMR) AF: 0.0295 AC: 1313 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26090

East Asian (EAS) AF: 0.197 AC: 7822 AN: 39626

South Asian (SAS) AF: 0.0347 AC: 2985 AN: 86124

European-Finnish (FIN) AF: 0.00749 AC: 373 AN: 49794

Middle Eastern (MID) AF: 0.00678 AC: 38 AN: 5606

European-Non Finnish (NFE) AF: 0.000473 AC: 526 AN: 1111400

Other (OTH) AF: 0.0206 AC: 1242 AN: 60306

GnomAD4 genome AF: 0.0281 AC: 4275 AN: 152214 Hom.: 218 Cov.: 33 AF XY: 0.0298 AC XY: 2218 AN XY: 74422

African (AFR) AF: 0.0601 AC: 2496 AN: 41526

American (AMR) AF: 0.0212 AC: 325 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1041 AN: 5140

South Asian (SAS) AF: 0.0413 AC: 199 AN: 4822

European-Finnish (FIN) AF: 0.00969 AC: 103 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 68010

Other (OTH) AF: 0.0260 AC: 55 AN: 2112

Alfa AF: 0.0123 Hom.: 29

Bravo AF: 0.0314

Asia WGS AF: 0.116 AC: 402 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Metaphyseal anadysplasia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		-0.14
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0
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: rs3918254; hg19: chr20-44640391; COSMIC: COSV63434192; COSMIC: COSV63434192;