rs9509

Variant names:

• chr20-46016514-T-C
• rs9509
• NM_004994.3:c.*146T>C

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.*146T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 709,702 control chromosomes in the GnomAD database, including 4,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1727 hom., cov: 31)
  • Exomes 𝑓: 0.059 (2483 hom.)
• Consequence: MMP9 NM_004994.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0710
• Publications: 24 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]

SLC12A5-AS1 (HGNC:53143): (SLC12A5 and MMP9 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 20-46016514-T-C is Benign according to our data. Variant chr20-46016514-T-C is described in ClinVar as Benign. ClinVar VariationId is 338563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP9	NM_004994.3	c.*146T>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000372330.3	NP_004985.2
SLC12A5-AS1	NR_147699.1	n.669-1726A>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP9	ENST00000372330.3	c.*146T>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_004994.3	ENSP00000361405.3
SLC12A5-AS1	ENST00000535913.2	n.669-1726A>G		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16982 AN: 152042 Hom.: 1724 Cov.: 31

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.0668

Gnomad FIN AF: 0.0282

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0902

GnomAD4 exome AF: 0.0591 AC: 32923 AN: 557542 Hom.: 2483 Cov.: 6 AF XY: 0.0561 AC XY: 16761 AN XY: 299022

African (AFR) AF: 0.256 AC: 3941 AN: 15424

American (AMR) AF: 0.185 AC: 6025 AN: 32560

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 1011 AN: 19064

East Asian (EAS) AF: 0.234 AC: 7493 AN: 31954

South Asian (SAS) AF: 0.0628 AC: 3833 AN: 61082

European-Finnish (FIN) AF: 0.0265 AC: 1088 AN: 41082

Middle Eastern (MID) AF: 0.0304 AC: 75 AN: 2470

European-Non Finnish (NFE) AF: 0.0227 AC: 7350 AN: 323756

Other (OTH) AF: 0.0699 AC: 2107 AN: 30150

GnomAD4 genome AF: 0.112 AC: 17001 AN: 152160 Hom.: 1727 Cov.: 31 AF XY: 0.113 AC XY: 8398 AN XY: 74392

African (AFR) AF: 0.259 AC: 10722 AN: 41476

American (AMR) AF: 0.162 AC: 2477 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 189 AN: 3470

East Asian (EAS) AF: 0.223 AC: 1151 AN: 5160

South Asian (SAS) AF: 0.0668 AC: 323 AN: 4832

European-Finnish (FIN) AF: 0.0282 AC: 299 AN: 10610

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0230 AC: 1563 AN: 68014

Other (OTH) AF: 0.0897 AC: 189 AN: 2106

Alfa AF: 0.0652 Hom.: 392

Bravo AF: 0.130

Asia WGS AF: 0.142 AC: 494 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 31, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Metaphyseal anadysplasia 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.2
DANN	Benign	0.89
PhyloP100		-0.071
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs9509; hg19: chr20-44645153;