Genetic Variant MMP15:p.Glu47Ala (chr16-58026490-A-C) – 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.140A>C(p.Glu47Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000813 in 1,230,038 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

MMP15
NM_002428.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0290

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=0.075047106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP15	NM_002428.4 link	c.140A>C	p.Glu47Ala	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.140A>C	p.Glu47Ala	missense_variant	Exon 1 of 10	1	NM_002428.4	ENSP00000219271.3		P51511

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.13e-7

AC:

AN:

1230038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

600422

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24428

American (AMR)

AF:

0.00

AC:

AN:

13052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18828

East Asian (EAS)

AF:

0.00

AC:

AN:

27366

South Asian (SAS)

AF:

0.00

AC:

AN:

57904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4350

European-Non Finnish (NFE)

AF:

0.00000100

AC:

AN:

998218

Other (OTH)

AF:

0.00

AC:

AN:

49900

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 21, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.140A>C (p.E47A) alteration is located in exon 1 (coding exon 1) of the MMP15 gene. This alteration results from a A to C substitution at nucleotide position 140, causing the glutamic acid (E) at amino acid position 47 to be replaced by an alanine (A). 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

0.078

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.063

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.54

M_CAP

Benign

0.019

MetaRNN

Benign

0.075

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.029

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.75

REVEL

Benign

0.073

Sift

Benign

0.45

Sift4G

Benign

0.56

Polyphen

0.015

Vest4

0.12

MutPred

0.52

Loss of helix (P = 0.0558);

MVP

0.49

MPC

2.0

ClinPred

0.051

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.080

gMVP

0.50

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over