rs3743563

Positions:

• chr16-58045261-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002428.4(MMP15):​c.1825G>A​(p.Gly609Arg) variant causes a missense change. The variant allele was found at a frequency of 0.217 in 1,608,266 control chromosomes in the GnomAD database, including 41,416 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3364 hom., cov: 33)
  • Exomes 𝑓: 0.22 (38052 hom.)
• Consequence: MMP15 NM_002428.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84

Genes affected

MMP15 (HGNC:7161): (matrix metallopeptidase 15) This gene encodes a member of the peptidase M10 family and membrane-type subfamily of matrix metalloproteinases (MMPs). Proteins in this 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. Members of this subfamily contain a transmembrane domain suggesting that these proteins are expressed at the cell surface rather than secreted. The encoded preproprotein is proteolytically processed to generate the mature protease. This protein may play a role in cancer progression. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037374198).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP15	NM_002428.4	c.1825G>A	p.Gly609Arg	missense_variant	10/10	ENST00000219271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP15	ENST00000219271.4	c.1825G>A	p.Gly609Arg	missense_variant	10/10	1	NM_002428.4	P1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28400 AN: 152108 Hom.: 3355 Cov.: 33

Gnomad AFR AF: 0.0649

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.170

GnomAD3 exomes AF: 0.237 AC: 56369 AN: 237644 Hom.: 8129 AF XY: 0.227 AC XY: 29208 AN XY: 128610

Gnomad AFR exome AF: 0.0614

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.341

Gnomad SAS exome AF: 0.169

Gnomad FIN exome AF: 0.320

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.220 AC: 319777 AN: 1456040 Hom.: 38052 Cov.: 34 AF XY: 0.216 AC XY: 156602 AN XY: 723798

Gnomad4 AFR exome AF: 0.0537

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.348

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.187 AC: 28421 AN: 152226 Hom.: 3364 Cov.: 33 AF XY: 0.194 AC XY: 14435 AN XY: 74436

Gnomad4 AFR AF: 0.0648

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.342

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.312

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.169

Alfa AF: 0.192 Hom.: 1290

Bravo AF: 0.185

TwinsUK AF: 0.203 AC: 751

ALSPAC AF: 0.213 AC: 821

ESP6500AA AF: 0.0701 AC: 308

ESP6500EA AF: 0.191 AC: 1645

ExAC AF: 0.216 AC: 26065

Asia WGS AF: 0.254 AC: 884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.77	P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.038
Sift	Benign	0.075	T
Sift4G	Benign	0.50	T
Polyphen		0.092	B
Vest4		0.081
MutPred		0.11		Gain of MoRF binding (P = 0.032);
MPC		0.65
ClinPred		0.021	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.1
Varity_R		0.091
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs3743563; hg19: chr16-58079165; COSMIC: COSV54679235; COSMIC: COSV54679235;