Variant 16-58040011-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002428.4(MMP15):c.577A>G(p.Lys193Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000681 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

MMP15
NM_002428.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.60

Variant links:

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]

MMP15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018102288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP15	NM_002428.4 linkuse as main transcript	c.577A>G	p.Lys193Glu	missense_variant	4/10	ENST00000219271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP15	ENST00000219271.4 linkuse as main transcript	c.577A>G	p.Lys193Glu	missense_variant	4/10	1	NM_002428.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000916

AC:

AN:

251172

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000354

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000384

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.577A>G (p.K193E) alteration is located in exon 4 (coding exon 4) of the MMP15 gene. This alteration results from a A to G substitution at nucleotide position 577, causing the lysine (K) at amino acid position 193 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.46

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.072

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.20

M_CAP

Benign

0.0044

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.050

MutationTaster

Benign

0.62

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

REVEL

Benign

0.078

Sift

Benign

0.13

Sift4G

Benign

0.54

Polyphen

0.014

Vest4

0.21

MVP

0.18

MPC

0.56

ClinPred

0.052

GERP RS

2.4

Varity_R

0.19

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over