Genetic Variant MMP15:p.Thr14Lys (chr16-58026391-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002428.4(MMP15):c.41C>A(p.Thr14Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000799 in 1,252,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T14R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

MMP15
NM_002428.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.190

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08301225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP15	NM_002428.4 link	c.41C>A	p.Thr14Lys	missense_variant	Exon 1 of 10	ENST00000219271.4	NP_002419.1	P51511A0A024R6U8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP15	ENST00000219271.4 link	c.41C>A	p.Thr14Lys	missense_variant	Exon 1 of 10	1	NM_002428.4	ENSP00000219271.3		P51511

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.99e-7

AC:

AN:

1252262

Hom.:

Cov.:

AF XY:

0.00000163

AC XY:

AN XY:

613044

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24648

American (AMR)

AF:

0.00

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18582

East Asian (EAS)

AF:

0.00

AC:

AN:

27872

South Asian (SAS)

AF:

0.0000166

AC:

AN:

60072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3614

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1018354

Other (OTH)

AF:

0.00

AC:

AN:

51514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.041

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.42

M_CAP

Benign

0.081

MetaRNN

Benign

0.083

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.19

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.35

REVEL

Benign

0.040

Sift

Uncertain

0.015

Sift4G

Benign

0.094

Polyphen

0.0

Vest4

0.24

MutPred

0.24

Gain of ubiquitination at T14 (P = 0.0138);

MVP

0.38

MPC

2.2

ClinPred

0.12

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.41

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

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16-58026391-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over