rs3918254

Positions:

• chr20-46011752-C-T

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.997+5C>T variant causes a splice donor 5th base, 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_donor_5th_base, intron
• Scores: Splicing: ADA: 0.00004573
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.138

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=-0.67).
• BP6: Variant 20-46011752-C-T is Benign according to our data. Variant chr20-46011752-C-T is described in ClinVar as [Benign]. Clinvar id is 338553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46011752-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP9	NM_004994.3	c.997+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000372330.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3	c.997+5C>T		splice_donor_5th_base_variant, intron_variant		1	NM_004994.3	P1

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

GnomAD3 exomes AF: 0.0298 AC: 7250 AN: 243486 Hom.: 458 AF XY: 0.0278 AC XY: 3678 AN XY: 132258

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 SAS exome AF: 0.0358

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

Gnomad4 AFR exome AF: 0.0634

Gnomad4 AMR exome AF: 0.0295

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.0347

Gnomad4 FIN exome AF: 0.00749

Gnomad4 NFE exome AF: 0.000473

Gnomad4 OTH exome AF: 0.0206

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

Gnomad4 AFR AF: 0.0601

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.0413

Gnomad4 FIN AF: 0.00969

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0115 Hom.: 27

Bravo AF: 0.0314

Asia WGS AF: 0.116 AC: 402 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2019	- -

Metaphyseal anadysplasia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs3918254; hg19: chr20-44640391; COSMIC: COSV63434192; COSMIC: COSV63434192;