Genetic Variant MMP15:p.His52Gln (chr16-58026506-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002428.4(MMP15):c.156T>G(p.His52Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,201,970 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MMP15
NM_002428.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.40

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045982838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP15	NM_002428.4 link	c.156T>G	p.His52Gln	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.156T>G	p.His52Gln	missense_variant	Exon 1 of 10	1	NM_002428.4	ENSP00000219271.3		P51511

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000108

AC:

AN:

1201970

Hom.:

Cov.:

AF XY:

0.0000103

AC XY:

AN XY:

583830

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23954

American (AMR)

AF:

0.00

AC:

AN:

11082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17332

East Asian (EAS)

AF:

0.00

AC:

AN:

27172

South Asian (SAS)

AF:

0.00

AC:

AN:

52482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4184

European-Non Finnish (NFE)

AF:

0.0000122

AC:

AN:

983122

Other (OTH)

AF:

0.0000206

AC:

AN:

48624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.036

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.25

M_CAP

Benign

0.014

MetaRNN

Benign

0.046

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.28

PhyloP100

-2.4

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.25

REVEL

Benign

0.014

Sift

Benign

0.48

Sift4G

Benign

0.44

Polyphen

0.0010

Vest4

0.10

MutPred

0.50

Loss of helix (P = 0.1706);

MVP

0.38

MPC

2.0

ClinPred

0.052

GERP RS

-6.9

Varity_R

0.053

gMVP

0.27

Mutation Taster

=86/14

polymorphism

(source)

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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16-58026506-T-G

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