chr20-46014472-G-A

Variant names:

• chr20-46014472-G-A
• rs17577
• NM_004994.3:c.2003G>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.2003G>A​(p.Arg668Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,549,446 control chromosomes in the GnomAD database, including 19,464 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R668G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (1940 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17524 hom.)
• Consequence: MMP9 NM_004994.3 missense, splice_region
• Scores: Splicing: ADA: 0.00001114
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.190
• Publications: 164 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 (MetaRNN=0.0029470026).
• BP6: Variant 20-46014472-G-A is Benign according to our data. Variant chr20-46014472-G-A is described in ClinVar as Benign. ClinVar VariationId is 338559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 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.2003G>A	p.Arg668Gln	missense splice_region	Exon 12 of 13	NP_004985.2	P14780
	SLC12A5-AS1	NR_147699.1		n.985C>T		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP9	ENST00000372330.3	TSL:1 MANE Select	c.2003G>A	p.Arg668Gln	missense splice_region	Exon 12 of 13	ENSP00000361405.3	P14780
	MMP9	ENST00000898203.1		c.1940G>A	p.Arg647Gln	missense splice_region	Exon 12 of 13	ENSP00000568262.1
	MMP9	ENST00000898204.1		c.1874G>A	p.Arg625Gln	missense splice_region	Exon 11 of 12	ENSP00000568263.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23790 AN: 152078 Hom.: 1942 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.159 AC: 24487 AN: 154326 AF XY: 0.169

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.0695

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.153 AC: 213619 AN: 1397250 Hom.: 17524 Cov.: 35 AF XY: 0.157 AC XY: 108526 AN XY: 689314

African (AFR) AF: 0.181 AC: 5718 AN: 31590

American (AMR) AF: 0.0745 AC: 2661 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4005 AN: 25182

East Asian (EAS) AF: 0.164 AC: 5856 AN: 35736

South Asian (SAS) AF: 0.290 AC: 22953 AN: 79222

European-Finnish (FIN) AF: 0.164 AC: 7794 AN: 47526

Middle Eastern (MID) AF: 0.155 AC: 881 AN: 5694

European-Non Finnish (NFE) AF: 0.143 AC: 154329 AN: 1078608

Other (OTH) AF: 0.162 AC: 9422 AN: 57988

GnomAD4 genome AF: 0.156 AC: 23806 AN: 152196 Hom.: 1940 Cov.: 32 AF XY: 0.158 AC XY: 11759 AN XY: 74422

African (AFR) AF: 0.177 AC: 7331 AN: 41524

American (AMR) AF: 0.0938 AC: 1435 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 546 AN: 3470

East Asian (EAS) AF: 0.148 AC: 765 AN: 5174

South Asian (SAS) AF: 0.298 AC: 1438 AN: 4820

European-Finnish (FIN) AF: 0.170 AC: 1806 AN: 10596

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10042 AN: 67988

Other (OTH) AF: 0.156 AC: 329 AN: 2112

Alfa AF: 0.146 Hom.: 6579

Bravo AF: 0.149

TwinsUK AF: 0.138 AC: 511

ALSPAC AF: 0.147 AC: 565

ESP6500AA AF: 0.159 AC: 614

ESP6500EA AF: 0.117 AC: 860

ExAC AF: 0.115 AC: 5306

Asia WGS AF: 0.210 AC: 728 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.048	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.33	N
PhyloP100		0.19
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.075
Sift	Benign	1.0	T
Sift4G	Benign	0.65	T
Polyphen		0.010	B
Vest4		0.049
ClinPred		0.0080	T
GERP RS		-9.3
Varity_R		0.071
gMVP		0.066
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
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: rs17577; hg19: chr20-44643111; COSMIC: COSV63433825;